Macrocyclic picolinamides as fungicides

ABSTRACT

The invention relates to macrocyclic picolinamides of Formula I and their use as fungicides.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. Nos. 61/920,942 and 61/920,946, each filed Dec. 26,2013, the disclosures of which are hereby incorporated by reference intheir entireties.

BACKGROUND & SUMMARY

Fungicides are compounds, of natural or synthetic origin, which act toprotect and/or cure plants against damage caused by agriculturallyrelevant fungi. Generally, no single fungicide is useful in allsituations. Consequently, research is ongoing to produce fungicides thatmay have better performance, are easier to use, and cost less.

The present disclosure relates to macrocyclic picolinamides and theiruse as fungicides. The compounds of the present disclosure may offerprotection against ascomycetes, basidiomycetes, deuteromycetes andoomycetes.

One embodiment of the present disclosure may include compounds ofFormula I:

wherein X is hydrogen or C(O)R₃;

Y is hydrogen, C(O)R₃, or Q;

Q is

R₁ is hydrogen, alkyl, alkenyl, aryl, alkoxy, or acyl, each optionallysubstituted with 0, 1 or multiple R₆;

R₂ is hydrogen, alkyl, aryl, —Si(R₅)₃, alkenyl, or acyl, each optionallysubstituted with 0, 1 or multiple R₆;

R₃ is alkoxy or benzyloxy, each optionally substituted with 0, 1, ormultiple R₆;

R₄ is hydrogen, —C(O)R₅, or —CH₂OC(O)R₅;

R₅ is alkyl, alkoxy, or aryl, each optionally substituted with 0, 1, ormultiple R₆;

R₆ is hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy, heteroaryl,heterocyclyl, or thioalkyl, each optionally substituted with 0, 1, ormultiple R₇; and

R₇ is hydrogen, alkyl, aryl, or halo.

Another embodiment of the present disclosure may include a fungicidalcomposition for the control or prevention of fungal attack comprisingthe compounds described above and a phytologically acceptable carriermaterial.

Yet another embodiment of the present disclosure may include a methodfor the control or prevention of fungal attack on a plant, the methodincluding the steps of applying a fungicidally effective amount of oneor more of the compounds described above to at least one of the fungus,the plant, and an area adjacent to the plant.

It will be understood by the those skilled in the art that the followingterms may include generic “R”-groups within their definitions, e.g.,“the term alkoxy refers to an —OR substituent”. It is also understoodthat within the definitions for the following terms, these “R” groupsare included for illustration purposes and should not be construed aslimiting or being limited by substitutions about Formula I.

The term “alkyl” refers to a branched, unbranched, or saturated cycliccarbon chain, including, but not limited to, methyl, ethyl, propyl,butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like. In some exemplaryembodiments, the term “alkyl” refers to a branched, unbranched, orsaturated cyclic carbon chain, including containing from 1 to 12 carbonatoms, from 1 to 6 carbons, or from 1 to 4 carbons.

The term “alkenyl” refers to a branched, unbranched or cyclic carbonchain containing one or more double bonds including, but not limited to,ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, and the like. In some exemplaryembodiments, the term “alkenyl” refers to a branched, unbranched, orsaturated cyclic carbon chain, including containing from 1 to 12 carbonatoms, from 1 to 6 carbons, or from 1 to 4 carbons.

The term “alkynyl” refers to a branched or unbranched carbon chaincontaining one or more triple bonds including, but not limited to,propynyl, butynyl and the like. In some exemplary embodiments, the term“alkynyl” refers to a branched, unbranched, or saturated cyclic carbonchain, including containing from 1 to 12 carbon atoms, from 1 to 6carbons, or from 1 to 4 carbons.

The term “aryl” refers to any aromatic, mono- or bi-cyclic, containing 0heteroatoms.

The term “heterocycle” refers to any aromatic or non-aromatic ring,mono- or bi-cyclic, containing one or more heteroatoms. In someexemplary embodiments, the one or more heteroatoms are independentlyselected from nitrogen, oxygen, phosphorous, and sulfur.

The term “alkoxy” refers to an —OR substituent.

The term “cyano” refers to a —C≡N substituent.

The term “hydroxyl” refers to an —OH substituent.

The term “amino” refers to a —NR₂ substituent.

The term “arylalkoxy” refers to —O(CH₂)_(n)—Ar where n is an integerselected from the list 1, 2, 3, 4, 5, or 6.

The term “haloalkoxy” refers to an —OR—X substituent, wherein X is Cl,F, Br, or I, or any combination thereof.

The term “haloalkyl” refers to an alkyl, which is substituted with Cl,F, I, or Br or any combination thereof.

The term “halogen” or “halo” refers to one or more halogen atoms,defined as F, Cl, Br, and I.

The term “nitro” refers to a —NO₂ substituent.

The term thioalkyl refers to an —SR substituent.

Throughout the disclosure, reference to the compounds of Formula I isread as also including diastereomers, enantiomers, and mixtures thereof.In another embodiment, Formula (I) is read as also including salts orhydrates thereof. Exemplary salts include, but are not limited to:hydrochloride, hydrobromide, and hydroiodide.

It is also understood by those skilled in the art that additionalsubstitution is allowable, unless otherwise noted, as long as the rulesof chemical bonding and strain energy are satisfied and the productstill exhibits fungicidal activity.

Another embodiment of the present disclosure is a use of a compound ofFormula I, for protection of a plant against attack by a phytopathogenicorganism or the treatment of a plant infested by a phytopathogenicorganism, comprising the application of a compound of Formula I, or acomposition comprising the compound to soil, a plant, a part of a plant,foliage, and/or roots.

Additionally, another embodiment of the present disclosure is acomposition useful for protecting a plant against attack by aphytopathogenic organism and/or treatment of a plant infested by aphytopathogenic organism comprising a compound of Formula I and aphytologically acceptable carrier material.

In one exemplary embodiment, a compound of Formula I is provided.

-   -   wherein    -   X is hydrogen or C(O)R₃;    -   Y is hydrogen, C(O)R₃, or Q;    -   Q is

-   -   R₁ is hydrogen, alkyl, alkenyl, aryl, alkoxy, or acyl, each        optionally substituted with 0, 1 or multiple R₆;    -   R₂ is hydrogen, alkyl, aryl, —Si(R₅)₃, alkenyl, or acyl, each        optionally substituted with 0, 1 or multiple R₆;    -   R₃ is alkoxy or benzyloxy, each optionally substituted with 0,        1, or multiple R₆;    -   R₄ is hydrogen, —C(O)R₅, or —CH₂OC(O)R₅;    -   R₅ is alkyl, alkoxy, or aryl, each optionally substituted with        0, 1, or multiple R₆; R₆ is hydrogen, alkyl, aryl, acyl, halo,        alkenyl, alkoxy, heteroaryl, heterocyclyl, or thioalkyl, each        optionally substituted with 0, 1, or multiple R₇; and    -   R₇ is hydrogen, alkyl, aryl, or halo.

In one more particular embodiment, X and Y are hydrogen. In another moreparticular embodiment of any of the above embodiments, R₁ is chosen fromalkyl and aryl, each optionally substituted with 0, 1 or multiple R₆. Inanother more particular embodiment of any of the above embodiments, R₂is chosen from hydrogen, alkyl, aryl, and acyl, each optionallysubstituted with 0, 1 or multiple R₆. In another more particularembodiment of any of the above embodiments, R₁ is chosen from alkyl andaryl, each optionally substituted with 0, 1 or multiple R₆, and R₂ ischosen from hydrogen, alkyl, aryl, and acyl, each optionally substitutedwith 0, 1 or multiple R₆. In another more particular embodiment of anyof the above embodiments, X is C(O)R₃ and Y is hydrogen. In another moreparticular embodiment of any of the above embodiments, R₁ is chosen fromalkyl and aryl, each optionally substituted with 0, 1 or multiple R₆. Inanother more particular embodiment of any of the above embodiments, R₂is chosen from hydrogen, alkyl, aryl, and acyl, each optionallysubstituted with 0, 1 or multiple R₆. In another more particularembodiment of any of the above embodiments, R₁ is chosen from alkyl andaryl, each optionally substituted with 0, 1 or multiple R₆, and R₂ ischosen from hydrogen, alkyl, aryl, and acyl, each optionally substitutedwith 0, 1 or multiple R₆. In another more particular embodiment of anyof the above embodiments, X is hydrogen and Y is Q. In another moreparticular embodiment of any of the above embodiments, R₄ is hydrogen.In another more particular embodiment of any of the above embodiments,R₁ is chosen from alkyl and aryl, each optionally substituted with 0, 1or multiple R₆. In another more particular embodiment of any of theabove embodiments, R₂ is chosen from hydrogen, alkyl, aryl, and acyl,each optionally substituted with 0, 1 or multiple R₆. In another moreparticular embodiment of any of the above embodiments, R₁ is chosen fromalkyl and aryl, each optionally substituted with 0, 1 or multiple R₆,and R₂ is chosen from hydrogen, alkyl, aryl, and acyl, each optionallysubstituted with 0, 1 or multiple R₆. In another more particularembodiment of any of the above embodiments, R₄ is —C(O)R₅ or—CH₂OC(O)R₅. In another more particular embodiment of any of the aboveembodiments, R₅ is chosen from alkyl and alkoxy, each optionallysubstituted with 0, 1, or multiple R₆. In another more particularembodiment of any of the above embodiments, R₁ is chosen from alkyl andaryl, each optionally substituted with 0, 1 or multiple R₆. In anothermore particular embodiment of any of the above embodiments, R₂ is chosenfrom hydrogen, alkyl, aryl, and acyl, each optionally substituted with0, 1 or multiple R₆. In another more particular embodiment of any of theabove embodiments, R₁ is chosen from alkyl and aryl, each optionallysubstituted with 0, 1 or multiple R₆, and R₂ is chosen from hydrogen,alkyl, aryl, and acyl, each optionally substituted with 0, 1 or multipleR₆. In another more particular embodiment of any of the aboveembodiments, R₅ is chosen from —CH₃, —CH₂OCH₂CH₃, and —CH₂CH₂OCH₃.

DETAILED DESCRIPTION

The compounds of the present disclosure may be applied by any of avariety of known techniques, either as the compounds or as formulationscomprising the compounds. For example, the compounds may be applied tothe roots or foliage of plants for the control of various fungi, withoutdamaging the commercial value of the plants. The materials may beapplied in the form of any of the generally used formulation types, forexample, as solutions, dusts, wettable powders, flowable concentrate, oremulsifiable concentrates.

Preferably, the compounds of the present disclosure are applied in theform of a formulation, comprising one or more of the compounds ofFormula I with a phytologically acceptable carrier. Concentratedformulations may be dispersed in water, or other liquids, forapplication, or formulations may be dust-like or granular, which maythen be applied without further treatment. The formulations can beprepared according to procedures that are conventional in theagricultural chemical art.

The present disclosure contemplates all vehicles by which one or more ofthe compounds may be formulated for delivery and use as a fungicide.Typically, formulations are applied as aqueous suspensions or emulsions.Such suspensions or emulsions may be produced from water-soluble,water-suspendible, or emulsifiable formulations which are solids,usually known as wettable powders; or liquids, usually known asemulsifiable concentrates, aqueous suspensions, or suspensionconcentrates. As will be readily appreciated, any material to whichthese compounds may be added may be used, provided it yields the desiredutility without significant interference with the activity of thesecompounds as antifungal agents.

Wettable powders, which may be compacted to form water-dispersiblegranules, comprise an intimate mixture of one or more of the compoundsof Formula I, an inert carrier and surfactants. The concentration of thecompound in the wettable powder may be from about 10 percent to about 90percent by weight based on the total weight of the wettable powder, morepreferably about 25 weight percent to about 75 weight percent. In thepreparation of wettable powder formulations, the compounds may becompounded with any finely divided solid, such as prophyllite, talc,chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein,gluten, montmorillonite clays, diatomaceous earths, purified silicatesor the like. In such operations, the finely divided carrier andsurfactants are typically blended with the compound(s) and milled.

Emulsifiable concentrates of the compounds of Formula I may comprise aconvenient concentration, such as from about 1 weight percent to about50 weight percent of the compound, in a suitable liquid, based on thetotal weight of the concentrate. The compounds may be dissolved in aninert carrier, which is either a water-miscible solvent or a mixture ofwater-immiscible organic solvents, and emulsifiers. The concentrates maybe diluted with water and oil to form spray mixtures in the form ofoil-in-water emulsions. Useful organic solvents include aromatics,especially the high-boiling naphthalenic and olefinic portions ofpetroleum such as heavy aromatic naphtha. Other organic solvents mayalso be used, for example, terpenic solvents, including rosinderivatives, aliphatic ketones, such as cyclohexanone, and complexalcohols, such as 2-ethoxyethanol.

Emulsifiers which may be advantageously employed herein may be readilydetermined by those skilled in the art and include various nonionic,anionic, cationic and amphoteric emulsifiers, or a blend of two or moreemulsifiers. Examples of nonionic emulsifiers useful in preparing theemulsifiable concentrates include the polyalkylene glycol ethers andcondensation products of alkyl and aryl phenols, aliphatic alcohols,aliphatic amines or fatty acids with ethylene oxide, propylene oxidessuch as the ethoxylated alkyl phenols and carboxylic esters solubilizedwith the polyol or polyoxyalkylene. Cationic emulsifiers includequaternary ammonium compounds and fatty amine salts. Anionic emulsifiersinclude the oil-soluble salts (e.g., calcium) of alkylaryl sulphonicacids, oil-soluble salts or sulfated polyglycol ethers and appropriatesalts of phosphated polyglycol ether.

Representative organic liquids which may be employed in preparing theemulsifiable concentrates of the compounds of the present disclosure arethe aromatic liquids such as xylene, propyl benzene fractions; or mixednaphthalene fractions, mineral oils, substituted aromatic organicliquids such as dioctyl phthalate; kerosene; dialkyl amides of variousfatty acids, particularly the dimethyl amides of fatty glycols andglycol derivatives such as the n-butyl ether, ethyl ether or methylether of diethylene glycol, the methyl ether of triethylene glycol,petroleum fractions or hydrocarbons such as mineral oil, aromaticsolvents, paraffinic oils, and the like; vegetable oils such as soy beanoil, rape seed oil, olive oil, castor oil, sunflower seed oil, coconutoil, corn oil, cotton seed oil, linseed oil, palm oil, peanut oil,safflower oil, sesame oil, tung oil and the like; esters of the abovevegetable oils; and the like. Mixtures of two or more organic liquidsmay also be employed in the preparation of the emulsifiable concentrate.Organic liquids include xylene, and propyl benzene fractions, withxylene being most preferred in some cases. Surface-active dispersingagents are typically employed in liquid formulations and in an amount offrom 0.1 to 20 percent by weight based on the combined weight of thedispersing agent with one or more of the compounds. The formulations canalso contain other compatible additives, for example, plant growthregulators and other biologically active compounds used in agriculture.

Aqueous suspensions comprise suspensions of one or more water-insolublecompounds of Formula I, dispersed in an aqueous vehicle at aconcentration in the range from about 1 to about 50 weight percent,based on the total weight of the aqueous suspension. Suspensions areprepared by finely grinding one or more of the compounds, and vigorouslymixing the ground material into a vehicle comprised of water andsurfactants chosen from the same types discussed above. Othercomponents, such as inorganic salts and synthetic or natural gums, mayalso be added to increase the density and viscosity of the aqueousvehicle.

The compounds of Formula I can also be applied as granular formulations,which are particularly useful for applications to the soil. Granularformulations generally contain from about 0.5 to about 10 weightpercent, based on the total weight of the granular formulation of thecompound(s), dispersed in an inert carrier which consists entirely or inlarge part of coarsely divided inert material such as attapulgite,bentonite, diatomite, clay or a similar inexpensive substance. Suchformulations are usually prepared by dissolving the compounds in asuitable solvent and applying it to a granular carrier which has beenpreformed to the appropriate particle size, in the range of from about0.5 to about 3 mm. A suitable solvent is a solvent in which the compoundis substantially or completely soluble. Such formulations may also beprepared by making a dough or paste of the carrier and the compound andsolvent, and crushing and drying to obtain the desired granularparticle.

Dusts containing the compounds of Formula I may be prepared byintimately mixing one or more of the compounds in powdered form with asuitable dusty agricultural carrier, such as, for example, kaolin clay,ground volcanic rock, and the like. Dusts can suitably contain fromabout 1 to about 10 weight percent of the compounds, based on the totalweight of the dust.

The formulations may additionally contain adjuvant surfactants toenhance deposition, wetting and penetration of the compounds onto thetarget crop and organism. These adjuvant surfactants may optionally beemployed as a component of the formulation or as a tank mix. The amountof adjuvant surfactant will typically vary from 0.01 to 1.0 percent byvolume, based on a spray-volume of water, preferably 0.05 to 0.5 volumepercent. Suitable adjuvant surfactants include, but are not limited toethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols,salts of the esters or sulphosuccinic acids, ethoxylatedorganosilicones, ethoxylated fatty amines, blends of surfactants withmineral or vegetable oils, crop oil concentrate (mineral oil(85%)+emulsifiers (15%)); nonylphenol ethoxylate;benzylcocoalkyldimethyl quaternary ammonium salt; blend of petroleumhydrocarbon, alkyl esters, organic acid, and anionic surfactant; C₉-C₁₁alkylpolyglycoside; phosphated alcohol ethoxylate; natural primaryalcohol (C₁₂-C₁₆) ethoxylate; di-sec-butylphenol EO-PO block copolymer;polysiloxane-methyl cap; nonylphenol ethoxylate+urea ammonium nitrate;emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate(8EO); tallow amine ethoxylate (15 EO); PEG(400) dioleate-99. Theformulations may also include oil-in-water emulsions such as thosedisclosed in U.S. patent application Ser. No. 11/495,228, the disclosureof which is expressly incorporated by reference herein.

The formulations may optionally include combinations that contain otherpesticidal compounds. Such additional pesticidal compounds may befungicides, insecticides, herbicides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds. Accordingly, in such embodiments, the otherpesticidal compound is employed as a supplemental toxicant for the sameor for a different pesticidal use. The compounds of Formula I and thepesticidal compound in the combination can generally be present in aweight ratio of from 1:100 to 100:1.

The compounds of the present disclosure may also be combined with otherfungicides to form fungicidal mixtures and synergistic mixtures thereof.The fungicidal compounds of the present disclosure are often applied inconjunction with one or more other fungicides to control a wider varietyof undesirable diseases. When used in conjunction with otherfungicide(s), the presently claimed compounds may be formulated with theother fungicide(s), tank-mixed with the other fungicide(s) or appliedsequentially with the other fungicide(s). Such other fungicides mayinclude 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin,Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus subtilis,Bacillus subtilis strain QST713, benalaxyl, benomyl,benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS) salt,bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen,blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole,bupirimate, calcium polysulfide, captafol, captan, carbendazim,carboxin, carpropamid, carvone, chlazafenone, chloroneb, chlorothalonil,chlozolinate, Coniothyrium minitans, copper hydroxide, copper octanoate,copper oxychloride, copper sulfate, copper sulfate (tribasic), cuprousoxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil,dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate),dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran,diethofencarb, difenoconazole, difenzoquat ion, diflumetorim,dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton,dinocap, diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine,dodine free base, edifenphos, enestrobin, enestroburin, epoxiconazole,ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil,fenpropidin, fenpropimorph, fenpyrazamine, fentin, fentin acetate,fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumorph,fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole,flusilazole, flusulfamide, flutianil, flutolanil, flutriafol,fluxapyroxad, folpet, formaldehyde, fosetyl, fosetyl-aluminium,fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates,GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalilsulfate, imibenconazole, iminoctadine, iminoctadine triacetate,iminoctadine tris(albesilate), iodocarb, ipconazole, ipfenpyrazolone,iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam,isotianil, kasugamycin, kasugamycin hydrochloride hydrate,kresoxim-methyl, laminarin, mancopper, mancozeb, mandipropamid, maneb,mefenoxam, mepanipyrim, mepronil, meptyl-dinocap, mercuric chloride,mercuric oxide, mercurous chloride, metalaxyl, metalaxyl-M, metam,metam-ammonium, metam-potassium, metam-sodium, metconazole,methasulfocarb, methyl iodide, methyl isothiocyanate, metiram,metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam,nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fattyacids), orysastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate,oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen,pentachlorophenol, pentachlorophenyl laurate, penthiopyrad,phenylmercury acetate, phosphonic acid, phthalide, picoxystrobin,polyoxin B, polyoxins, polyoxorim, potassium bicarbonate, potassiumhydroxyquinoline sulfate, probenazole, prochloraz, procymidone,propamocarb, propamocarb hydrochloride, propiconazole, propineb,proquinazid, prothioconazole, pyraclostrobin, pyrametostrobin,pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox,pyrimethanil, pyriofenone, pyroquilon, quinoclamine, quinoxyfen,quintozene, Reynoutria sachalinensis extract, sedaxane, silthiofam,simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodiumpentachlorophenoxide, spiroxamine, sulfur, SYP-Z048, tar oils,tebuconazole, tebufloquin, tecnazene, tetraconazole, thiabendazole,thifluzamide, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl,tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole,tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole,validamycin, valifenalate, valiphenal, vinclozolin, zineb, ziram,zoxamide, Candida oleophila, Fusarium oxysporum, Gliocladium spp.,Phlebiopsis gigantea, Streptomyces griseoviridis, Trichoderma spp.,(RS)-N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate,1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine,4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine,azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox,bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl,bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmiumcalcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone,chloraniformethan, chlorfenazole, chlorquinox, climbazole, copperbis(3-phenylsalicylate), copper zinc chromate, cufraneb, cuprichydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram,decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol,dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin,drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf,fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole,furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin,halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos,isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam,methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride,myclozolin, N-3,5-dichlorophenyl-succinimide,N-3-nitrophenylitaconimide, natamycin,N-ethylmercurio-4-toluenesulfonanilide, nickelbis(dimethyldithiocarbamate), OCH, phenylmercurydimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb;prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor,pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole,rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor,thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid,triamiphos, triarimol, triazbutil, trichlamide, urbacid, zarilamid, andany combinations thereof.

Additionally, the compounds described herein may be combined with otherpesticides, including insecticides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds to form pesticidal mixtures and synergistic mixturesthereof. The fungicidal compounds of the present disclosure may beapplied in conjunction with one or more other pesticides to control awider variety of undesirable pests. When used in conjunction with otherpesticides, the presently claimed compounds may be formulated with theother pesticide(s), tank-mixed with the other pesticide(s) or appliedsequentially with the other pesticide(s). Typical insecticides include,but are not limited to: 1,2-dichloropropane, abamectin, acephate,acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile,alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin,allyxycarb, alpha-cypermethrin, alpha-ecdysone, alpha-endosulfan,amidithion, aminocarb, amiton, amiton oxalate, amitraz, anabasine,athidathion, azadirachtin, azamethiphos, azinphos-ethyl,azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin,bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin,bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bistrifluron,borax, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos,bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos,butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate,calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran,carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan,cartap, cartap hydrochloride, chlorantraniliprole, chlorbicyclen,chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride,chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron,chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos,chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chromafenozide,cinerin I, cinerin II, cinerins, cismethrin, cloethocarb, closantel,clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate,copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos,crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate,cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin,cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran,deltamethrin, demephion, demephion-O, demephion-S, demeton,demeton-methyl, demeton-O, demeton-O-methyl, demeton-S,demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos,diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos,dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor,dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos,dimetilan, dinex, dinex-diclexine, dinoprop, dinosam, dinotefuran,diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton,dithicrofos, d-limonene, DNOC, DNOC-ammonium, DNOC-potassium,DNOC-sodium, doramectin, ecdysterone, emamectin, emamectin benzoate,EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane,eprinomectin, esdepalléthrine, esfenvalerate, etaphos, ethiofencarb,ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate,ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide,etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor,fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb,fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion,fenthion, fenthion-ethyl, fenvalerate, fipronil, flonicamid,flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim,flufenoxuron, flufenprox, fluvalinate, fonofos, formetanate, formetanatehydrochloride, formothion, formparanate, formparanate hydrochloride,fosmethilan, fospirate, fosthietan, furathiocarb, furethrin,gamma-cyhalothrin, gamma-HCH, halfenprox, halofenozide, HCH, HEOD,heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon,hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin,indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos,isodrin, isofenphos, isofenphos-methyl, isoprocarb, isoprothiolane,isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos,juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan,kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos,lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben,mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride,mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion,methiocarb, methocrotophos, methomyl, methoprene, methoxychlor,methoxyfenozide, methyl bromide, methyl isothiocyanate,methylchloroform, methylene chloride, metofluthrin, metolcarb,metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime,mipafox, mirex, molosultap, monocrotophos, monomehypo, monosultap,morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine,nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron,noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos,oxydisulfoton, para-dichlorobenzene, parathion, parathion-methyl,penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin,phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor,phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos,pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite,potassium thiocyanate, pp′-DDT, prallethrin, precocene I, precocene II,precocene III, primidophos, profenofos, profluralin, promacyl,promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos,prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos,pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyridaben,pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate,pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl,quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla,schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodiumfluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide,spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron,sulcofuron-sodium, sulfluramid, sulfotep, sulfoxaflor, sulfurylfluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenozide,tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, TEPP,terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos,tetramethrin, tetramethylfluthrin, theta-cypermethrin, thiacloprid,thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiocyclam oxalate,thiodicarb, thiofanox, thiometon, thiosultap, thiosultap-disodium,thiosultap-monosodium, thuringiensin, tolfenpyrad, tralomethrin,transfluthrin, transpermethrin, triarathene, triazamate, triazophos,trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron,trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb,zeta-cypermethrin, zolaprofos, and any combinations thereof.

Additionally, the compounds described herein may be combined withherbicides that are compatible with the compounds of the presentdisclosure in the medium selected for application, and not antagonisticto the activity of the present compounds to form pesticidal mixtures andsynergistic mixtures thereof. The fungicidal compounds of the presentdisclosure may be applied in conjunction with one or more herbicides tocontrol a wide variety of undesirable plants. When used in conjunctionwith herbicides, the presently claimed compounds may be formulated withthe herbicide(s), tank-mixed with the herbicide(s) or appliedsequentially with the herbicide(s). Typical herbicides include, but arenot limited to: 4-CPA; 4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB;2,4-DEB; 2,4-DEP; 3,4-DP; 2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor,acifluorfen, aclonifen, acrolein, alachlor, allidochlor, alloxydim,allyl alcohol, alorac, ametridione, ametryn, amibuzin, amicarbazone,amidosulfuron, aminocyclopyrachlor, aminopyralid, amiprofos-methyl,amitrole, ammonium sulfamate, anilofos, anisuron, asulam, atraton,atrazine, azafenidin, azimsulfuron, aziprotryne, barban, BCPC,beflubutamid, benazolin, bencarbazone, benfluralin, benfuresate,bensulfuron, bensulide, bentazone, benzadox, benzfendizone, benzipram,benzobicyclon, benzofenap, benzofluor, benzoylprop, benzthiazuron,bicyclopyrone, bifenox, bilanafos, bispyribac, borax, bromacil,bromobonil, bromobutide, bromofenoxim, bromoxynil, brompyrazon,butachlor, butafenacil, butamifos, butenachlor, buthidazole, buthiuron,butralin, butroxydim, buturon, butylate, cacodylic acid, cafenstrole,calcium chlorate, calcium cyanamide, cambendichlor, carbasulam,carbetamide, carboxazole chlorprocarb, carfentrazone, CDEA, CEPC,chlomethoxyfen, chloramben, chloranocryl, chlorazifop, chlorazine,chlorbromuron, chlorbufam, chloreturon, chlorfenac, chlorfenprop,chlorflurazole, chlorflurenol, chloridazon, chlorimuron, chlornitrofen,chloropon, chlorotoluron, chloroxuron, chloroxynil, chlorpropham,chlorsulfuron, chlorthal, chlorthiamid, cinidon-ethyl, cinmethylin,cinosulfuron, cisanilide, clethodim, cliodinate, clodinafop, clofop,clomazone, clomeprop, cloprop, cloproxydim, clopyralid, cloransulam,CMA, copper sulfate, CPMF, CPPC, credazine, cresol, cumyluron,cyanatryn, cyanazine, cycloate, cyclosulfamuron, cycloxydim, cycluron,cyhalofop, cyperquat, cyprazine, cyprazole, cypromid, daimuron, dalapon,dazomet, delachlor, desmedipham, desmetryn, di-allate, dicamba,dichlobenil, dichloralurea, dichlormate, dichlorprop, dichlorprop-P,diclofop, diclosulam, diethamquat, diethatyl, difenopenten, difenoxuron,difenzoquat, diflufenican, diflufenzopyr, dimefuron, dimepiperate,dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimexano,dimidazon, dinitramine, dinofenate, dinoprop, dinosam, dinoseb,dinoterb, diphenamid, dipropetryn, diquat, disul, dithiopyr, diuron,DMPA, DNOC, DSMA, EBEP, eglinazine, endothal, epronaz, EPTC, erbon,esprocarb, ethalfluralin, ethametsulfuron, ethidimuron, ethiolate,ethofumesate, ethoxyfen, ethoxysulfuron, etinofen, etnipromid,etobenzanid, EXD, fenasulam, fenoprop, fenoxaprop, fenoxaprop-P,fenoxasulfone, fenteracol, fenthiaprop, fentrazamide, fenuron, ferroussulfate, flamprop, flamprop-M, flazasulfuron, florasulam, fluazifop,fluazifop-P, fluazolate, flucarbazone, flucetosulfuron, fluchloralin,flufenacet, flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac,flumioxazin, flumipropyn, fluometuron, fluorodifen, fluoroglycofen,fluoromidine, fluoronitrofen, fluothiuron, flupoxam, flupropacil,flupropanate, flupyrsulfuron, fluridone, flurochloridone, fluroxypyr,flurtamone, fluthiacet, fomesafen, foramsulfuron, fosamine, furyloxyfen,glufosinate, glufosinate-P, glyphosate, halosafen, halosulfuron,haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone, hexaflurate,hexazinone, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin,imazethapyr, imazosulfuron, indanofan, indaziflam, iodobonil,iodomethane, iodosulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam,isocarbamid, isocil, isomethiozin, isonoruron, isopolinate, isopropalin,isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole,isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, linuron,MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, medinoterb,mefenacet, mefluidide, mesoprazine, mesosulfuron, mesotrione, metam,metamifop, metamitron, metazachlor, metazosulfuron, metflurazon,methabenzthiazuron, methalpropalin, methazole, methiobencarb,methiozolin, methiuron, methometon, methoprotryne, methyl bromide,methyl isothiocyanate, methyldymron, metobenzuron, metobromuron,metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, molinate,monalide, monisouron, monochloroacetic acid, monolinuron, monuron,morfamquat, MSMA, naproanilide, napropamide, naptalam, neburon,nicosulfuron, nipyraclofen, nitralin, nitrofen, nitrofluorfen,norflurazon, noruron, OCH, orbencarb, ortho-dichlorobenzene,orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxapyrazon,oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat,pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol,pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisopham,phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate,picloram, picolinafen, pinoxaden, piperophos, potassium arsenite,potassium azide, potassium cyanate, pretilachlor, primisulfuron,procyazine, prodiamine, profluazol, profluralin, profoxydim,proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop,propazine, propham, propisochlor, propoxycarbazone, propyrisulfuron,propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, prynachlor,pydanon, pyraclonil, pyraflufen, pyrasulfotole, pyrazolynate,pyrazosulfuron, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor,pyridafol, pyridate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac,pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine,quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron,saflufenacil, S-metolachlor, sebuthylazine, secbumeton, sethoxydim,siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodiumazide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone,sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA,tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim,terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn,tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin,thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb,tiocarbazil, tioclorim, topramezone, tralkoxydim, triafamone,tri-allate, triasulfuron, triaziflam, tribenuron, tricamba, triclopyr,tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron,trifop, trifopsime, trihydroxytriazine, trimeturon, tripropindan,tritac, tritosulfuron, vernolate, and xylachlor.

Another embodiment of the present disclosure is a method for the controlor prevention of fungal attack. This method comprises applying to thesoil, plant, roots, foliage, or locus of the fungus, or to a locus inwhich the infestation is to be prevented (for example applying to cerealor grape plants), a fungicidally effective amount of one or more of thecompounds of Formula I. The compounds are suitable for treatment ofvarious plants at fungicidal levels, while exhibiting low phytotoxicity.The compounds may be useful both in a protectant and/or an eradicantfashion.

The compounds have been found to have significant fungicidal effectparticularly for agricultural use. Many of the compounds areparticularly effective for use with agricultural crops and horticulturalplants.

It will be understood by those in the art that the efficacy of thecompound for the foregoing fungi establishes the general utility of thecompounds as fungicides.

The compounds have broad ranges of activity against fungal pathogens.Exemplary pathogens may include, but are not limited to, causing agentof wheat leaf blotch (Mycosphaerella graminicola; impect stage: Septoriatritici), wheat brown rust (Puccinia triticina), wheat stripe rust(Puccinia striiformis), scab of apple (Venturia inaequalis), powderymildew of grapevine (Uncinula necator), barley scald (Rhynchosporiumsecalis), blast of rice (Magnaporthe grisea), rust of soybean(Phakopsora pachyrhizi), glume blotch of wheat (Leptosphaeria nodorum),powdery mildew of wheat (Blumeria graminis f. sp. tritici), powderymildew of barley (Blumeria graminis f. sp. hordei), powdery mildew ofcucurbits (Erysiphe cichoracearum), anthracnose of cucurbits (Glomerellalagenarium), leaf spot of beet (Cercospora beticola), early blight oftomato (Alternaria solani), and spot blotch of barley (Cochliobolussativus). The exact amount of the active material to be applied isdependent not only on the specific active material being applied, butalso on the particular action desired, the fungal species to becontrolled, and the stage of growth thereof, as well as the part of theplant or other product to be contacted with the compound. Thus, all thecompounds, and formulations containing the same, may not be equallyeffective at similar concentrations or against the same fungal species.

The compounds are effective in use with plants in a disease-inhibitingand phytologically acceptable amount. The term “disease-inhibiting andphytologically acceptable amount” refers to an amount of a compound thatkills or inhibits the plant disease for which control is desired, but isnot significantly toxic to the plant. This amount will generally be fromabout 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm beingpreferred. The exact concentration of compound required varies with thefungal disease to be controlled, the type of formulation employed, themethod of application, the particular plant species, climate conditions,and the like. A suitable application rate is typically in the range fromabout 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams per squaremeter, g/m²).

Any range or desired value given herein may be extended or alteredwithout losing the effects sought, as is apparent to the skilled personfor an understanding of the teachings herein.

The compounds of Formula I may be made using well-known chemicalprocedures. Intermediates not specifically mentioned in this disclosureare either commercially available, may be made by routes disclosed inthe chemical literature, or may be readily synthesized from commercialstarting materials utilizing standard procedures.

General Schemes

The following schemes illustrate approaches to generating picolinamidecompounds of Formula (I). The following descriptions and examples areprovided for illustrative purposes and should not be construed aslimiting in terms of substituents or substitution patterns.

Compounds of Formula 1.5, where R₁ is as originally defined, can beprepared according to the methods outlined in Scheme 1, steps a-g.Compounds of Formula 1.1, where R₁ is as originally defined, can beobtained by reaction of the dianion of an ester of Formula 1.0 formed bytreatment with lithium diisopropyl amide (LDA) at −50° C., with an alkylhalide or allyl halide in a solvent such as tetrahydrofuran (THF) atcryogenic temperatures such as −78° C., as shown in a. Compounds ofFormula 1.2, where R₁ is as originally defined, can be obtained bytreating compounds of Formula 1.1, where R₁ is an alkenyl functionality,with hydrogen gas in the presence of a catalyst such as palladium oncarbon (Pd/C) in a solvent such as ethyl acetate (EtOAc), as shown in b.Compounds of Formula 1.3, where R₁ is as originally defined, can beprepared from compounds of Formula 1.1, where R₁ is as defined above,and Formula 1.2, where R₁ is as defined above, by treating with analkylating agent such as 4-methoxybenzyl 2,2,2-trichloroacetimidate inthe presence of an acid such as camphor sulfonic acid (CSA) in a solventsuch as dichloromethane (DCM), as depicted in c. Aldehydes of Formula1.4, where R₁ is as originally defined, can be obtained by the reductionof esters of Formula 1.3, where R₁ is as defined above, using a catalystsuch as chlorobis(cyclooctene)iridium(I) dimer in the presence of areducing agent such as diethylsilane (Et₂SiH) in a solvent such as DCM,as shown in d. Aldehydes of Formula 1.4, where R₁ is as originallydefined, can also be obtained by reduction of esters of Formula 1.3,where R₁ is as defined above, using hydride reducing agents, such aslithium aluminum hydride (LiAlH₄, LAH) in ethereal solvents, givingalcohols of Formula 1.6, where R₁ is as defined above, as depicted in e.Oxidation of alcohols of Formula 1.6, where R₁ is as defined above,using oxidation reagents such as sulfur trioxide-pyridine complex(SO₃-pyridine/dimethyl sulfoxide (DMSO)) in solvents such as DCM,furnish the aldehydes of Formula 1.4, where R₁ is as originally defined,as depicted in f. The addition of metallated alkenes such as vinylmagnesium bromide to aldehydes of Formula 1.4, where R₁ is as definedabove, in a solvent such as THF at −78° C., affords allylic alcohols ofFormula 1.5, where R₁ is as originally defined, as depicted in g.

Compounds of Formulas 2.0 and 2.1, where R₁ and R₂ are as originallydefined, but R₂ is not acyl or hydrogen, can be prepared as shown inScheme 2, steps a-b. Alcohols of Formula 1.5, where R₁ is as originallydefined, can be alkylated to give compounds of Formula 2.0, where R₁ andR₂ are as defined above, by deprotonation with a base such as sodiumhydride (NaH) in an aprotic solvent such as N,N-dimethylformamide (DMF),followed by treatment with an alkylating agent, such ascyclopropylmethyl bromide, at an elevated temperature such as 50° C., asshown in a. Alternatively, alcohols of Formula 1.5, where R₁ is asdefined above, can be arylated by treating with an arylating agent suchas triphenylbismuth(V)diacetate in the presence of a copper catalystsuch as diacetoxycopper and a base such asN,N-dicyclohexyl-N-methylamine in a solvent such as toluene at anelevated temperature such as 60° C. to give compounds of Formula 2.1,where R₁ and R₂ are as defined above, as depicted in b.

Compounds of Formula 3.5, where R₁ and R₂ are as originally defined, butR₂ is not acyl or hydrogen, can be prepared according to the methodsoutlined in Scheme 3, steps a-d. Alcohols of Formula 3.1, where R₁ andR₂ are as originally defined, but R₂ is not acyl or hydrogen, can beobtained from compounds of Formula 3.0, where R₁ and R₂ are asoriginally defined, but R₂ is not acyl or hydrogen, by ozonolysis at acryogenic temperature such as −78° C. in a solvent mixture such as DCMand methanol (MeOH), followed by treating with a reducing agent such assodium borohydride (NaBH₄), as shown in a. Alcohols of Formula 3.1,where R₁ and R₂ are as defined above, can be treated with protectedaziridines of Formula 3.2 in the presence of a Lewis acid such as borontrifluoride-diethyl etherate (BF₃—Et₂O) at 0° C., in a halogenatedsolvent such as DCM, as shown in b, to afford compounds of Formula 3.3,where R₁ and R₂ are as originally defined, but R₂ is not acyl orhydrogen. Compounds of Formula 3.4, where R₁ and R₂ are as originallydefined, but R₂ is not acyl or hydrogen, can be obtained from compoundsof Formula 3.3, where R₁ and R₂ are as defined above, by treating withan oxidant such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) in asolvent mixture such as DCM and water, as shown in c. Treating compoundsof Formula 3.4, where R₁ and R₂ are as defined above, with a hydroxidebase such as lithium hydroxide (LiOH) in a solvent mixture such as THFand water, as depicted in d, provides compounds of Formula 3.5, where R₁and R₂ are as defined above.

Compounds of Formula 4.0, where R₁ and R₂ are as originally defined, butR₂ is not acyl or hydrogen, can be prepared according to the methodsoutlined in Scheme 4. Compounds of Formula 4.0, where R₁ and R₂ are asdefined above, can be obtained by the addition of a solution ofcompounds of Formula 3.5, where R₁ and R₂ are as originally defined, butR₂ is not acyl or hydrogen, in a halogenated solvent such as DCM to amixture of a base, such as 4-dimethylaminopyridine (DMAP), and a mixedanhydride, such as 2-methyl-6-nitrobenzoic anhydride (MNBA), in anaprotic solvent such as DCM over a period of 4-12 hours, as shown in a.

Compounds of Formula 5.2, where R₁ is as originally defined and R₂ isacyl, can be prepared according to the methods outlined in Scheme 5,steps a-b. Compounds of the Formula 5.1, where R₁ is as originallydefined, can be prepared from compounds of Formula 5.0, where R₁ is asoriginally defined and R₂ is benzyl, by hydrogenolysis using a metalcatalyst such as palladium on carbon (Pd/C) in the presence of hydrogengas. Compounds of Formula 5.2, where R₁ and R₂ are as defined above, canbe prepared from compounds of Formula 5.1, where R₁ and R₂ are asdefined above, by reacting with an acylating agent such ascyclopropanecarbonyl chloride in the presence of base such astriethylamine (TEA) and DMAP in a halogenated solvent such as DCM.

Compounds of Formula 6.3, where R₁ and R₂ are as originally defined, butR₂ is not hydrogen, can be prepared through the methods shown in Scheme6, steps a-c. Compounds of Formula 6.1, where R₁ and R₂ are asoriginally defined, but R₂ is not hydrogen, can be prepared by treatingcompounds of Formula 6.0, where R₁ and R₂ are as defined above, but R₂is not hydrogen or an alkoxy moiety, with an acid, such as a 4.0 Molar(M) hydrogen chloride (HCl) solution in dioxane, in a solvent such asDCM, as shown in a. The resulting hydrochloride salt may be neutralizedprior to use to give the free amine or neutralized in situ in step c.Compounds of Formula 6.2. where R₁ is as defined above and R₂ is analkyl substituted with an alkoxy moiety, can be prepared from compoundsof Formula 6.1, where R₁ and R₂ are as defined above, by treating withtrimethylsilyl trifluoromethanesulfonate and a base such as 2,6-lutidinein a halogenated solvent DCM, followed by quenching with MeOH as shownin b. The resulting triflate salt may be neutralized prior to use togive the free amine or neutralized in situ in step c. Compounds ofFormula 6.3, where R₁ and R₂ are as defined above, can be prepared fromcompounds of Formula 6.1, where R₁ and R₂ are as defined above, or fromcompounds of Formula 6.2, where R₁ and R₂ are as defined above, bytreatment with 3-hydroxy-4-methoxypicolinic acid in the presence of abase, such as diisopropylethylamine, and a peptide coupling reagent,such as benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate (PyBOP) orO-(7-azabenzotriazol-1-yl)-N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), in an halogenated solvent such as DCM, asshown in c.

Compounds of Formula 7.0, where R₁, R₂ and R₄ are as originally defined,but R₂ is not hydrogen, can be prepared by the method shown in Scheme 7.Compounds of Formula 7.0, where R₁, R₂, and R₄ are as defined above, canbe prepared from compounds of Formula 6.3, where R₁ and R₂ are asoriginally defined, but R₂ is not hydrogen, by treatment with theappropriate alkyl halide with or without a reagent such as sodium iodide(NaI) and an alkali carbonate base such as sodium carbonate (Na₂CO₃) orpotassium carbonate (K₂CO₃) in a solvent such as acetone or by treatmentwith an acyl halide in the presence of an amine base, such as pyridine,TEA, DMAP, or mixtures thereof in an aprotic solvent such as DCM, asshown in a.

EXAMPLES Example 1 Step 1: Preparation of (S)-methyl2-((S)-1-hydroxyethyl)-5-methylhex-4-enoate

To a solution of diisopropylamine (19.93 milliliters (mL), 142millimoles (mmol)) in anhydrous THF (99 mL) at −50° C. (deficient dryice/acetone bath) was added n-butyllithium (n-BuLi; 54.3 mL, 130 mmol,2.5 M in hexanes). This solution was removed from the cold bath for 15minutes (min), then re-cooled to −50° C. To the lithium diisopropylamide(LDA) was added a solution of (S)-methyl 3-hydroxybutanoate (6.64 ml,59.3 mmol) in THF (20.0 mL) dropwise over 15 min using a cannula. Thissolution was allowed to warm to −30° C. over 30 min, stirred at −30° C.for 1 h, and recooled to −78° C. To the enolate was added a solution of1-bromo-3-methylbut-2-ene (13.7 mL, 119 mmol) in anhydrous1,2-dimethoxyethane (20.0 mL, 193 mmol) dropwise over 15 min. The coldbath was at −60° C. after 1 h at which time the reaction flask wasremoved from the bath and stirred without cooling for 1.5 h. Thereaction was quenched by the addition of sat. aq. ammonium chloride(NH₄Cl; 50 mL), diluted with EtOAc (50 mL), and the phases wereseparated. The aqueous phase was further extracted with EtOAc (2×50 mL)and the combined organic extracts were washed with sat. aq. sodiumchloride (NaCl, brine; 50 mL), dried over sodium sulfate Na₂SO₄,filtered, and concentrated to dryness. The crude residue was purified byflash column chromatography (120 grams (g) silica gel (SiO₂), 0→40%EtOAc/hexanes) to afford the title compound (9.5 g, 51.0 mmol, 86%) as aslightly yellow oil: IR (thin film) 3452, 2971, 2929, 1730, 1437, 1198,1160 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.11-5.01 (m, 1H), 3.92 (p, J=6.3Hz, 1H), 3.70 (s, 3H), 2.78 (s, 1H), 2.46-2.28 (m, 3H), 1.69 (d, J=1.4Hz, 3H), 1.62 (s, 3H), 1.23 (d, J=6.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃)δ 175.54, 134.14, 120.30, 67.78, 52.72, 51.52, 27.90, 25.73, 21.46,17.64.

Example 1 Step 2: Preparation of (S)-methyl2-((S)-1-hydroxyethyl)-5-methylhexanoate

To a well stirred solution of (S)-methyl2-((S)-1-hydroxyethyl)-5-methylhex-4-enoate (9.5 g, 51.0 mmol) in MeOH(51 mL) was added 10% Pd/C (0.543 g, 5.10 mmol). The reaction was putunder a hydrogen atmosphere (balloon) and stirred at room temperaturefor 20 h. The mixture was filtered through a plug of Celite® and theplug was washed with MeOH (20 mL). The filtrate and washes werecombined, the solvent was removed under reduced pressure, and theresidue was dissolved in DCM (50 mL). The solution was passed through aphase separator to remove residual water (H₂O), and the solvent wasremoved under reduced pressure to afford the title compound (9.45 g,50.2 mmol, 98%) as a slightly yellow oil: IR (thin film) 3451, 2954,2871, 1736, 1719, 1169 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 3.91 (p, J=6.4Hz, 1H), 3.72 (s, 3H), 2.77 (s, 1H), 2.36 (ddd, J=9.2, 6.3, 5.0 Hz, 1H),1.72-1.45 (m, 3H), 1.28-1.05 (m, 5H), 0.88 (dd, J=6.6, 3.2 Hz, 6H); ¹³CNMR (75 MHz, CDCl₃) δ 176.13, 68.55, 53.29, 51.67, 36.55, 28.16, 27.37,22.74, 22.44, 21.68.

Example 1 Step 3: Preparation of (S)-methyl2-((S)-1-((4-methoxybenzyl)oxy)ethyl)-5-methylhexanoate

To a solution of (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhexanoate(5.00 g, 26.6 mmol) and((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonicacid (camphorsulfonic acid, CSA; 0.617 g, 2.66 mmol) in DCM (53.1 mL)was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (8.27 mL, 39.8mmol) at 0° C. The reaction mixture was removed from the cold bath andstirred at room temperature for 17 h. Hexane (50 mL) was added to thereaction and the precipitate was removed by filtration. The solids werewashed with hexanes (2×10 mL), Celite® (2 scoopula tip-fulls) was addedto the combined filtrate and washes, and the solvent was removed underreduced pressure. The resulting adsorbed material was directly loadedonto a column and purified using flash column chromatography (80 g SiO₂,0→35% EtOAc/hexanes) to afford the title compound (6.3 g, 20.4 mmol,77%) as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.16 (m, 2H),6.89-6.79 (m, 2H), 4.49 (d, J=11.2 Hz, 1H), 4.33 (d, J=11.1 Hz, 1H),3.75 (s, 3H), 3.74-3.62 (m, 4H), 2.49 (ddd, J=10.7, 8.2, 4.0 Hz, 1H),1.62-1.40 (m, 3H), 1.23-1.16 (m, 3H), 1.16-1.03 (m, 2H), 0.87 (d, J=3.9Hz, 3H), 0.85 (d, J=3.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 175.03,159.10, 130.63, 129.14, 113.62, 76.16, 70.71, 55.11, 52.64, 51.25,36.58, 27.97, 26.00, 22.69, 22.17, 17.08; ESIMS m/z 331 ([M+Na]⁺).

Example 1 Steps 4 and 5: Preparation of(3S,4R)-4-((S)-1-((4-methoxy-benzyl)oxy)ethyl)-7-methyloct-1-en-3-ol and(3R,4R)-4-((S)-1-((4-methoxybenzyl)oxy)ethyl)-7-methyloct-1-en-3-ol

Step 4

To a solution of (S)-methyl2-((S)-1-((4-methoxybenzyl)oxy)ethyl)-5-methylhexanoate (6.00 g, 19.5mmol) and chlorobis(cyclooctene)-iridium(I) dimer (0.349 g, 0.389 mmol)in dry DCM (19.5 mL) was slowly added Et₂SiH (3.76 mL, 29.2 mmol) at 0°C. The flask was removed from the cold bath and the reaction was stirredat room temperature for 20 h under nitrogen (N₂). The reaction mixturewas transferred via cannula to an ice-cooled mixture of diethyl ether(Et₂O; 60 mL) and 2 Normal (N) HCl (20 mL) over 15 min. The mixture wasremoved from the cold bath and stirred at room temperature for 30 min.The phases were separated and the aq. phase was further extracted withEt₂O (2×50 mL). The organics were combined, washed with sat. aq. sodiumbicarbonate (NaHCO₃; 25 mL) and brine (25 mL), dried over Na₂SO₄,filtered, and the filtrate treated with Celite® (5 scoopula tip-fulls).The solvent was removed under reduced pressure and the resultingadsorbed material was directly loaded onto a column and purified usingflash column chromatography (120 g SiO₂, 0→75% EtOAc/hexanes) to affordthe intermediate aldehyde,(S)-2-((S)-1-((4-methoxybenzyl)oxy)ethyl)-5-methylhexanal.

Step 5

The intermediate aldehyde was dissolved in THF (30 mL), the mixture wascooled to −78° C., vinylmagnesium bromide (29.2 mL, 29.2 mmol, 1M inTHF) was slowly added, and the resulting solution was stirred for 30min. The reaction was removed from the cold bath, stirred at roomtemperature for 30 min, and quenched by the addition of sat. aq. NH₄Cl(30 mL). The phases were separated, and the aq. phase was furtherextracted with Et₂O (3×50 mL). The combined organics were dried overNa₂SO₄, filtered, and concentrated to dryness. The residue was dissolvedin DCM (20 mL) and the resulting solution was treated with Celite® (5scoopula tip-fulls). The solvent was removed under reduced pressure andthe resulting adsorbed material was directly loaded onto a column andpurified using flash column chromatography (220 g SiO₂, 0→15%acetone/hexanes) to afford the individual diastereomers as colorlessoils:

(3S,4R)-4-((S)-1-((4-methoxybenzyl)oxy)ethyl)-7-methyloct-1-en-3-ol(2.35 g, 7.67 mmol, 39%): ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.19 (m, 2H),6.91-6.82 (m, 2H), 5.84 (ddd, J=17.2, 10.6, 4.7 Hz, 1H), 5.29 (app dt,J=17.2, 1.9 Hz, 1H), 5.16 (app dt, J=10.6, 1.9 Hz, 1H), 4.58 (d, J=11.0Hz, 1H), 4.53-4.45 (m, 1H), 4.27 (d, J=10.9 Hz, 1H), 3.83 (d, J=4.3 Hz,1H), 3.79 (s, 3H), 3.76-3.65 (m, 1H), 1.52-1.26 (m, 7H), 1.20-1.06 (m,2H), 0.85 (app dd, J=6.6, 2.2 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ159.33, 139.16, 130.02, 129.54, 114.61, 113.88, 76.55, 72.08, 70.65,55.26, 49.31, 37.35, 28.25, 23.51, 22.63, 22.52, 17.71; ESIMS m/z 329([M+Na]⁺).

(3R,4R)-4-((S)-1-((4-methoxybenzyl)oxy)ethyl)-7-methyloct-1-en-3-ol(1.48 g, 4.83 mmol, 25%): ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.22 (m, 2H),6.91-6.83 (m, 2H), 5.89 (ddd, J=17.1, 10.3, 6.7 Hz, 1H), 5.24 (ddd,J=17.2, 1.8, 1.2 Hz, 1H), 5.12 (ddd, J=10.4, 1.8, 1.1 Hz, 1H), 4.58 (d,J=11.1 Hz, 1H), 4.35 (d, J=11.1 Hz, 1H), 4.22-4.13 (m, 1H), 3.80 (s,3H), 3.70 (p, J=6.3 Hz, 1H), 3.66 (d, J=3.2 Hz, 1H), 1.56 (tt, J=6.8,5.2 Hz, 1H), 1.49-1.24 (m, 6H), 1.19-1.08 (m, 2H), 0.84 (dd, J=6.7, 2.0Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 159.24, 140.20, 130.22, 129.41,115.17, 113.87, 78.10, 75.83, 70.43, 55.28, 48.98, 36.07, 28.53, 26.08,22.52, 17.93; ESIMS m/z 329 ([M+Na]⁺).

Example 1 Step 6: Preparation of(2R,3S)-2-benzyl-3-((4-methoxybenzyl)-oxy)butan-1-ol

To a stirred suspension of LAH in anhydrous Et₂O (140 mL) was added(2S,3S)-methyl 2-benzyl-3-((4-methoxybenzyl)oxy)butanoate dissolved inEt₂O (104 mL) dropwise at 0° C. The reaction was stirred at 0° C. for 15min, followed by warming to room temperature and stirring for 1 h. Thereaction was recooled to 0° C. and carefully quenched by thesimultaneous dropwise addition of H₂O (2.8 mL) and 1N sodium hydroxide(NaOH; 2.8 mL). The mixture was filtered and the aluminum salts werewashed with Et₂O (50 mL). The filtrate was treated with Celite® (20 g)and concentrated to give a solid. The adsorbed material was purifiedusing flash column chromatography (120 g SiO₂ column, 0→60%EtOAc/hexane) to afford the title compound (5.38 g, 74%) as a clear oil:¹H NMR (400 MHz, CDCl₃) δ 7.30-7.10 (m, 7H), 6.93-6.84 (m, 2H), 4.59 (d,J=11.2 Hz, 1H), 4.30 (d, J=11.2 Hz, 1H), 3.89 (app dt, J=11.4, 2.9 Hz,1H), 3.80 (s, 3H), 3.66 (app qd, J=6.2, 4.3 Hz, 1H), 3.50 (ddd, J=11.5,6.9, 4.7 Hz, 1H), 2.93-2.85 (m, 1H), 2.75 (app qd, J=13.7, 7.5 Hz, 2H),1.76 (dddt, J=10.9, 6.6, 4.3, 2.3 Hz, 1H), 1.29 (d, J=6.3 Hz, 3H); ¹³CNMR (101 MHz, CDCl₃) δ 159.32, 140.61, 130.35, 129.39, 129.20, 128.36,125.97, 113.93, 70.70, 62.36, 55.31, 47.81, 35.11, 17.67; ESIMS m/z 323([M+Na]⁺).

Example 1 Step 7: (2S,3S)-2-benzyl-3-((4-methoxybenzyl)oxy)butanal

To a solution of (2R,3S)-2-benzyl-3-((4-methoxybenzyl)oxy)butan-1-ol(5.38 g, 17.91 mmol) in CH₂Cl₂ (90 mL) in a nitrogen flushed 250 mLround bottomed flask was added DMSO (17.9 mL, 25.24 mmol) and TEA (12.5mL, 90 mmol) via syringe followed by sulfur trioxode-pyridine complex(8.55 g, 53.7 mmol) in three equal portions at 0° C. under N₂. Thereaction was removed from the cold bath and allowed to warm to roomtemperature, and stirred for 2 h. The reaction was diluted with ice cold0.5 N HCl (100 mL) and EtOAc (150 mL). The phases were separated and theorganic phase was washed with sat. aq. NaHCO₃ (50 mL) and brine (50 mL).The solution was dried over magnesium sulfate (MgSO₄), filtered, andconcentrated to afford the title compound (5.3 g, 96%) as a yellow oil:¹H NMR (400 MHz, CDCl₃) δ 9.78 (d, J=2.8 Hz, 1H), 7.29-7.09 (m, 7H),6.89 (d, J=8.7 Hz, 2H), 4.56 (d, J=11.3 Hz, 1H), 4.34 (d, J=11.3 Hz,1H), 3.82 (s, 3H), 3.03 (dd, J=14.0, 8.2 Hz, 1H), 2.87 (dd, J=14.0, 6.4Hz, 2H), 2.78-2.55 (m, 1H), 1.29 (d, J=6.4 Hz, 3H); ESIMS m/z 321.3([M+Na]⁺).

Example 1 Step 8: Preparation of(3S,4R,5S)-4-benzyl-5-(4-methoxybenzyl)oxy)-hex-1-en-3-ol

To a 200 mL round-bottomed flask equipped with a magnetic stir bar wereadded (2S,3S)-2-benzyl-3-((4-methoxybenzyl)oxy)butanal (5.34 g, 17.90mmol) and THF (36 mL). The flask was cooled to −78° C. andvinylmagnesium bromide (1.0 M in THF, 36 mL, 36 mmol) was added via asyringe. The reaction was maintained at −78° C. for 1.5 h, quenched withsat. aq. NH₄Cl (25 mL) at −78° C., and then removed from the cold bath.After warming to room temperature, the biphasic mixture was diluted withEtOAc (100 mL), and the phases were separated. The organic phase waswashed with brine (30 mL), dried over MgSO₄, filtered, and concentrated.The oil was purified by flash column chromatography (120 g SiO₂ column,0→100% EtOAc/hexanes) to afford the pure desired isomer (1.18 g), and amixture of the isomers (2.53 g). The mixture was re-purified by flashcolumn chromatography (80 g SiO₂ column, 0→15% acetone/hexanes) toafford clean separation of the isomers in a 2.23:1 ratio ofdiastereomers.

(3S,4R,5S)-4-Benzyl-5-((4-methoxybenzyl)oxy)hex-1-en-3-ol (2.88 g, 49%):¹H NMR (400 MHz, CDCl₃) δ 7.28-7.17 (m, 5H), 7.05-6.98 (m, 2H),6.92-6.84 (m, 2H), 5.91 (ddd, J=17.1, 10.6, 4.4 Hz, 1H), 5.36 (dt,J=17.2, 1.9 Hz, 1H), 5.23 (dt, J=10.6, 1.8 Hz, 1H), 4.65-4.59 (m, 1H),4.56 (d, J=10.9 Hz, 1H), 4.21 (d, J=11.0 Hz, 1H), 3.89 (d, J=2.7 Hz,1H), 3.78 (s, 3H), 3.65 (qd, J=6.3, 3.7 Hz, 1H), 2.72 (d, J=7.3 Hz, 2H),1.78-1.70 (m, 1H), 1.25 (d, J=6.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ159.46, 141.10, 139.22, 130.09, 129.57, 129.23, 128.39, 125.91, 115.02,114.01, 75.38, 70.99, 70.74, 55.33, 50.95, 31.46, 17.72; ESIMS m/z 349([M+Na]⁺).

(3R,4R,5S)-4-Benzyl-5-((4-methoxybenzyl)oxy)hex-1-en-3-ol (1.3 g, 22%):¹H NMR (300 MHz, CDCl₃) δ 7.33-7.04 (m, 7H), 6.96-6.78 (m, 2H), 5.96(ddd, J=17.2, 10.4, 5.5 Hz, 1H), 5.25 (dt, J=17.2, 1.7 Hz, 1H), 5.11(dt, J=10.5, 1.6 Hz, 1H), 4.56 (d, J=11.4 Hz, 1H), 4.31 (d, J=11.4 Hz,1H), 4.28-4.22 (m, 1H), 3.82 (s, 3H), 3.72-3.65 (m, 1H), 2.86-2.87 (m,3H), 2.06-1.96 (m, 1H), 1.27 (d, J=6.4 Hz, 3H): ESIMS m/z 349.3([M+Na]⁺).

Example 2 Step 1: Preparation of1-methoxy-4-((((2S,3S)-6-methyl-3-((S)-1-phenoxyallyl)heptan-2-yl)oxy)methyl)benzene

A toluene (12.0 mL) solution of(3S,4R)-4-((S)-1-(4-methoxybenzyl)oxy)ethyl)-7-methyloct-1-en-3-ol (1.10g, 3.59 mmol), N-cyclohexyl-N-methylcyclohexanamine (1.14 mL, 5.38mmol), triphenylbismuth diacetate (3.01 g, 5.38 mmol), and copper(II)acetate (0.130 g, 0.718 mmol) was heated to 50° C. and stirred at thistemperature for 16 h. Additional triphenylbismuth diacetate (1.00 g) wasadded to push the reaction to completion, and after a total reactiontime of 38 h, the reaction mixture was cooled to room temperature,loaded onto a Celite® plug and purified by flash column chromatography(40 g SiO₂, 0→15% EtOAc/hexanes) to afford the title compound (1.10 g,2.30 mmol, 64%): ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.20 (m, 3H), 6.99-6.86(m, 4H), 6.76-6.68 (m, 2H), 5.85 (ddd, J=17.4, 10.8, 4.8 Hz, 1H),5.27-5.16 (m, 2H), 5.09 (ddt, J=4.8, 3.2, 1.7 Hz, 1H), 4.39 (d, J=10.6Hz, 1H), 4.09 (d, J=10.6 Hz, 1H), 3.76 (s, 3H), 3.64 (dq, J=8.0, 6.2 Hz,1H), 1.68-1.56 (m, 2H), 1.55-1.42 (m, 1H), 1.41-1.17 (m, 6H), 0.88 (appdd, J=6.6, 1.4 Hz, 6H); ESIMS m/z 405 ([M+Na]⁺).

Example 2 Step 2: Preparation of1-methoxy-4-((((2S,3S)-6-methyl-3-((S)-1-propoxyallyl)heptan-2-yl)oxy)methyl)benzene

To a solution of(3S,4R)-4-((S)-1-((4-methoxybenzyl)oxy)ethyl)-7-methyloct-1-en-3-ol(1.40 g, 4.57 mmol) and potassium 2-methylpropan-2-olate (0.564 g, 5.03mmol) in THF (30.5 mL) was added propyl 4-methylbenzenesulfonate (2.15mL, 11.4 mmol). The reaction was stirred at room temperature for 72 h,diluted with H₂O (15 mL), and the phases were separated. The aq. phasewas further extracted with Et₂O (3×25 mL), and the combined organicswere washed with brine (15 mL), dried over Na₂SO₄, filtered, and thefiltrate was treated with Celite® (4 scoopula tip-fulls). The solventwas removed under reduced pressure and the resulting adsorbed materialwas directly loaded onto a column and purified using flash columnchromatography (80 g SiO₂, 0→15% EtOAc/hexanes) to afford the titlecompound (1.30 g, 3.36 mmol, 74%) as a colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 7.30-7.22 (m, 2H), 6.91-6.83 (m, 2H), 5.77-5.63 (m, 1H),5.20-5.14 (m, 1H), 5.13 (d, J=1.1 Hz, 1H), 4.50-4.35 (m, 2H), 3.85-3.77(m, 4H), 3.61 (p, J=6.3 Hz, 1H), 3.43 (app tt, J=9.8, 6.6 Hz, 1H), 3.12(app dt, J=9.1, 6.6 Hz, 1H), 1.69-1.20 (m, 8H), 1.15 (d, J=6.3 Hz, 3H),0.91 (t, J=7.4 Hz, 3H), 0.87 (app dd, J=6.6, 1.1 Hz, 6H); ¹³C NMR (101MHz, CDCl₃) δ 158.98, 138.54, 131.33, 129.16, 116.04, 113.69, 81.66,75.17, 70.57, 70.12, 55.26, 47.97, 38.70, 28.65, 23.69, 23.24, 22.63,16.76, 10.90; ESIMS m/z 371 ([M+Na]⁺).

Example 2 Step 3: Preparation of1-((((2S,3S)-3-((S)-1-(benzyloxy)allyl)-6-methylheptan-2-yl)oxy)methyl)-4-methoxybenzene

To a solution of(3S,4R)-4-((S)-1-((4-methoxybenzyl)oxy)ethyl)-7-methyloct-1-en-3-ol(2.34 g, 7.64 mmol) in DMF (15.3 mL) was added NaH (0.611 g, 15.3 mmol,60% dispersion in mineral oil) at 0° C. After 20 min, benzyl bromide(2.27 mL, 19.1 mmol) was added and the reaction was stirred at 0° C. for20 min, warmed to 45° C., and stirred at this temperature for 16 h. Thereaction was cooled to room temperature and quenched with sat. aq. NH₄Cl(40 mL). The mixture was extracted with Et₂O (3×50 mL), and the combinedorganics were washed with brine (40 mL), dried over Na₂SO₄, filtered,and concentrated to dryness. The residue was purified using flash columnchromatography (120 g SiO₂, 0→20% EtOAc/hexanes) to afford the titlecompound (2.75 g, 6.93 mmol, 91%) as a colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 7.38-7.34 (m, 2H), 7.32-7.25 (m, 3H), 7.22-7.17 (m, 2H),6.87-6.78 (m, 2H), 5.78 (ddd, J=17.4, 9.9, 7.3 Hz, 1H), 5.27-5.18 (m,2H), 4.58 (d, J=12.4 Hz, 1H), 4.42 (d, J=11.2 Hz, 1H), 4.29 (d, J=11.2Hz, 1H), 4.26 (d, J=11.9 Hz, 1H), 4.04-3.96 (m, 1H), 3.77 (s, 3H), 3.64(p, J=6.3 Hz, 1H), 1.73-1.63 (m, 1H), 1.55-1.42 (m, 2H), 1.43-1.21 (m,3H), 1.15 (d, J=6.3 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H); ¹³C NMR (101 MHz,CDCl₃) δ 158.92, 139.07, 137.94, 131.19, 129.17, 128.19, 127.77, 127.47,116.82, 113.65, 81.13, 75.03, 70.36, 70.07, 55.22, 48.17, 38.66, 28.62,23.67, 22.61, 16.84; ESIMS m/z 419 ([M+Na]⁺).

Example 3 Step 1. Preparation of(2R,3S)-3-((S)-1-((4-methoxybenzyl)oxy)ethyl)-6-methyl-2-propoxyheptan-1-ol

To a solution of1-methoxy-4-((((2S,3S)-6-methyl-3-((S)-1-propoxyallyl)heptan-2-yl)oxy)methyl)benzene(710 mg, 2.04 mmol) in DCM (20 mL) and MeOH (5 mL) were added NaHCO₃(34.2 mg, 0.407 mmol) and1-(((E)-(4-(((E)-phenyldiazenyl)phenyl)diazenyl)-naphthalen-2-ol (twodrops, as a 1% w/v solution in DCM). The resulting faint-pink coloredreaction mixture was cooled to −78° C. (dry ice/acetone) and the flaskwas vented to a trap containing a sat. aq. potassium iodide solution.Oxygen was bubbled through the solution for two min and then ozone wasbubbled through the reaction mixture until the pink color dissipated(about 10 min). The ozone addition was stopped and the system was purgedwith oxygen for about 5 min. The system was placed under N₂ and NaBH₄(231 mg, 6.11 mmol) was added along with additional MeOH (10 mL). Thereaction mixture was stirred at room temperature for 16 h, quenched withsat. aq. NH₄Cl (10 mL), and extracted with DCM (3×10 mL). The combinedorganic extracts were passed through a phase separator cartridge toremove residual H₂O and then treated with Celite® (2 scoopulatip-fulls). The solvent was removed under reduced pressure and theresulting adsorbed material was directly loaded onto a column andpurified using flash column chromatography (40 g SiO₂, 0→35%EtOAc/hexanes) to afford the title compound (578 mg, 1.64 mmol, 80%) asa colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.21 (m, 2H), 6.90-6.83(m, 2H), 4.53 (d, J=11.2 Hz, 1H), 4.33 (d, J=11.2 Hz, 1H), 3.79 (s, 3H),3.65-3.54 (m, 3H), 3.51-3.38 (m, 3H), 2.54-2.46 (m, 1H), 1.74-1.32 (m,6H), 1.29-1.14 (m, 5H), 0.91 (t, J=7.4 Hz, 3H), 0.87 (app dd, J=6.6, 1.1Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 159.06, 130.78, 129.22, 113.72,81.26, 74.95, 72.16, 70.18, 62.89, 55.23, 45.05, 37.94, 28.55, 25.14,23.45, 22.62, 22.59, 17.24, 10.76; ESIMS m/z 375 ([M+Na]⁺).

Example 3 Step 2. Preparation of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(((2R,3S)-3-((S)-1-(((4-methoxybenzyl)oxy)ethyl)-6-methyl-2-propoxyheptyl)oxy)propanoate

To a 0° C. solution of (S)-1-tert-butyl 2-methylaziridine-1,2-dicarboxylate (325 mg, 1.62 mmol) and(2R,3S)-3-((S)-1-((4-methoxybenzyl)oxy)ethyl)-6-methyl-2-propoxyheptan-1-ol(475 mg, 1.35 mmol) in DCM (6.74 mL) was added BF₃—OEt₂ (34.2microliters (μL), 0.269 mmol). After 45 min at this temperature, sat.aq. NaHCO₃ (10 mL) was added and the phases were separated. The aq.phase was further extracted with DCM (3×10 mL) and the combined organicextracts were washed with brine (8 mL), dried over Na₂SO₄, filtered, andthe filtrate was treated with Celite® (3 scoopula tip-fulls). Thesolvent was removed under reduced pressure and the resulting adsorbedmaterial was directly loaded onto a column and purified using flashcolumn chromatography (80 g SiO₂, 0→20% acetone/hexanes) to afford thetitle compound (325 mg, 0.516 mmol, 38%) as a colorless oil: ¹H NMR (400MHz, CDCl₃) δ 7.29-7.21 (m, 2H), 6.90-6.84 (m, 2H), 5.43 (d, J=8.8 Hz,1H), 4.49 (d, J=11.3 Hz, 1H), 4.43-4.29 (m, 2H), 3.92-3.84 (m, 1H), 3.79(s, 3H), 3.72 (s, 3H), 3.66-3.42 (m, 6H), 3.31 (app dt, J=9.0, 6.7 Hz,1H), 1.60-1.46 (m, 3H), 1.46-1.16 (m, 17H), 0.93-0.84 (m, 9H); ¹³C NMR(101 MHz, CDCl₃) δ 171.15, 159.03, 155.54, 131.21, 129.13, 113.72,79.83, 78.74, 75.23, 73.76, 72.69, 71.33, 70.07, 55.25, 54.12, 52.31,45.63, 38.45, 28.62, 28.32, 24.03, 23.51, 22.61, 22.56, 17.15, 10.75;ESIMS m/z 576 ([M+Na]⁺).

Example 3 Step 3. Preparation of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(((2R,3S)-3-((S)-1-hydroxyethyl)-6-methyl-2-propoxyheptyl)oxy)propanoate

To a solution of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(((2R,3S)-3-((S)-1-((4-methoxybenzyl)oxy)ethyl)-6-methyl-2-propoxyheptyl)oxy)propanoate(375 mg, 0.677 mmol) in H₂O (0.205 mL) and DCM (2.05 mL) at 0° C. wasadded DDQ (161 mg, 0.711 mmol). The mixture was vigorously stirred atthis temperature for 1 h and then treated with 1N NaOH (677 μL, 0.677mmol) and H₂O (8 mL). The phases were separated and the aq. phase wasfurther extracted with DCM (3×15 mL). The combined organic extracts werewashed with brine (8 mL), dried over Na₂SO₄, filtered, and the filtratewas treated with Celite® (2 scoopula tip-fulls). The solvent was removedunder reduced pressure and the resulting adsorbed material was directlyloaded onto a column and purified using flash column chromatography (40g SiO₂, 0→60% EtOAc/hexanes) to afford the title compound (244 mg, 0.563mmol, 83%) as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 5.45 (d, J=8.8Hz, 1H), 4.53-4.33 (m, 1H), 3.95-3.87 (m, 1H), 3.82-3.71 (m, 6H),3.70-3.44 (m, 5H), 1.63-1.35 (m, 14H), 1.31-1.09 (m, 6H), 1.00-0.80 (m,9H); ¹³C NMR (101 MHz, CDCl₃) δ 171.02, 155.42, 80.23, 79.89, 72.20,72.12, 71.49, 68.97, 54.01, 52.34, 46.18, 37.44, 28.27, 24.79, 23.27,22.54, 22.49, 22.16, 10.57; ESIMS m/z 456 ([M+Na]⁺).

Example 3 Step 4. Preparation of(S)-2-((tert-butoxycarbonyl)amino)-3-((2R,3S)-3-((S)-1-hydroxyethyl)-6-methyl-2-propoxyheptyl)oxy)propanoicacid

To a solution of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(((2R,3S)-3-((S)-1-hydroxyethyl)-6-methyl-2-propoxyheptyl)oxy)propanoate(240 mg, 0.554 mmol) in THF (3.69 mL) and H₂O (1.85 mL) was addedLiOH.H₂O (67.7 mg, 1.61 mmol), and the reaction was stirred at roomtemperature for 4 h and then diluted with EtOAc (10 mL) and 0.2N HCl (10mL). The phases were separated and the aq. phase was further extractedwith EtOAc (3×15 mL). The combined organic extracts were washed withbrine (5 mL), dried over Na₂SO₄, filtered, and concentrated to drynessto afford the title compound (220 mg, 0.524 mmol, 95%) as a colorlessoil: ¹H NMR (400 MHz, CDCl₃) δ 7.87-7.62 (m, 2H), 5.54 (d, J=8.2 Hz,1H), 4.43-4.35 (m, 1H), 3.97-3.89 (m, 1H), 3.89-3.77 (m, 1H), 3.75-3.42(m, 6H), 1.64-1.32 (m, 14H), 1.28-1.09 (m, 6H), 0.96-0.84 (m, 9H); ¹³CNMR (101 MHz, CDCl₃) δ 174.07, 155.58, 80.32, 79.83, 72.19, 71.68,71.61, 69.32, 54.10, 46.34, 37.40, 28.32, 28.27, 24.98, 23.17, 22.55,22.47, 21.99, 10.56; ESIMS m/z 418 ([M−H]⁻).

Example 4 Preparation of tert-butyl((3S,7R,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxy-1,5-dioxonan-3-yl)carbamate(39)

A solution of(S)-2-((tert-butoxycarbonyl)amino)-3-((2R,3S)-3-((S)-1-hydroxyethyl)-6-methyl-2-propoxyheptyl)oxy)propanoicacid (220 mg, 0.524 mmol) in anhydrous DCM (30 mL) was added over 8 h,using a syringe pump, to a stirred solution of MNBA (361 mg, 1.05 mmol)and DMAP (384 mg, 3.15 mmol) in DCM (52 mL) at room temperature. Themixture was stirred for 10 h and then treated with Celite® (4 scoopulatip-fulls). The solvent was removed under reduced pressure and theresulting adsorbed material was directly loaded onto a column andpurified using flash column chromatography (40 g SiO₂, 0→50%EtOAc/hexanes) to afford the title compound (178 mg, 0.443 mmol, 85%) asa white solid: mp 74-77° C.; ¹H NMR (400 MHz, CDCl₃) δ 5.35 (d, J=8.4Hz, 1H), 5.11-4.99 (m, 1H), 4.66-4.57 (m, 1H), 3.98-3.86 (m, 2H),3.83-3.74 (m, 1H), 3.61-3.50 (m, 2H), 3.26-3.16 (m, 1H), 3.06-2.97 (m,1H), 1.87-1.74 (m, 1H), 1.75-1.61 (m, 1H), 1.62-1.39 (m, 12H), 1.41-1.27(m, 4H), 1.23-1.07 (m, 2H), 0.95-0.85 (m, 9H); ¹³C NMR (101 MHz, CDCl₃)δ 171.14, 155.20, 81.02, 79.95, 79.70, 75.26, 73.61, 71.33, 54.38,50.13, 33.86, 28.73, 28.29, 25.98, 23.19, 22.55, 22.47, 19.86, 10.75;ESIMS m/z 424 ([M+Na]⁺).

Example 5 Step 1. Preparation of tert-butyl((3S,7R,8R,9S)-7-hydroxy-8-isopentyl-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate(66)

A solution of tert-butyl((3S,7R,8S,9S)-7-(benzyloxy)-8-isopentyl-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate(420 mg, 0.934 mmol) and 10% Pd/C (49.7 mg, 0.467 mmol) in THF (9.34 mL)was stirred under a hydrogen atmosphere (balloon) for 22 h. The balloonwas refilled with hydrogen and stirred for an additional 16 h. Thereaction mixture was filtered through a pad of Celite® and the pad waswashed with EtOAc (2×15 mL). The combined filtrate and washes wereconcentrated to dryness to afford the title compound (315 mg, 0.806mmol, 86%) as a white solid: mp 112-115° C.; ¹H NMR (400 MHz, CDCl₃) δ5.41 (d, J=8.2 Hz, 1H), 4.95 (dq, J=9.7, 6.3 Hz, 1H), 4.74-4.46 (m, 1H),4.00 (dd, J=11.8, 6.8 Hz, 1H), 3.80-3.70 (m, 2H), 3.62-3.50 (m, 2H),2.28-2.14 (m, 1H), 1.88-1.76 (m, 1H), 1.69-1.57 (m, 1H), 1.53-1.37 (m,14H), 1.30-1.07 (m, 2H), 0.88 (app d, J=6.6 Hz, 6H); ¹³C NMR (101 MHz,CDCl₃) δ 171.70, 155.18, 80.10, 79.79, 73.84, 72.74, 53.48, 50.52,33.91, 28.60, 28.28, 26.28, 22.55, 22.45, 20.01; ESIMS m/z 382([M+Na]⁺).

Example 5 Step 2. Preparation of(3S,7R,8S,9S)-3-((tert-butoxycarbonyl)amino)-8-isopentyl-9-methyl-2-oxo-1,5-dioxonan-7-ylcyclopropanecarboxylate (49)

To a solution of tert-butyl((3S,7R,8R,9S)-7-hydroxy-8-isopentyl-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate(300 mg, 0.835 mmol) and DMAP (102 mg, 0.835 mmol) in anhydrous pyridine(2.50 mL) was added cyclopropanecarbonyl chloride (87 μL, 0.960 mmol) at0° C., and the reaction was stirred at this temperature for 10 min andthen removed from the cold bath. The reaction was stirred at roomtemperature for 3 h, treated with additional cyclopropanecarbonylchloride (37.9 μL, 0.417 mmol), and stirred for an additional 1 h. Thereaction was diluted with Et₂O (10 mL), followed by sat. aq. NH₄Cl (10mL), and the phases were separated. The aq. phase was further extractedwith Et₂O (2×10 mL), and the combined organic extracts were washed withbrine (5 mL), dried over Na₂SO₄, filtered, and concentrated to dryness.The crude residue was loaded onto a silica gel and purified using flashcolumn chromatography (40 g SiO₂, 0→50% EtOAc/hexanes) to afford thetitle compound (296 mg, 0.692 mmol, 83%) as a white solid: mp 92-95° C.;¹H NMR (400 MHz, CDCl₃) δ 5.31 (d, J=8.2 Hz, 1H), 5.09-4.97 (m, 1H),4.75-4.60 (m, 2H), 3.99-3.89 (m, 1H), 3.78-3.63 (m, 3H), 2.13-2.01 (m,1H), 1.65-1.54 (m, 1H), 1.53-1.26 (m, 15H), 1.19-1.04 (m, 2H), 1.05-0.93(m, 2H), 0.90-0.82 (m, 8H); ¹³C NMR (101 MHz, CDCl₃) δ 173.70, 171.24,155.15, 80.04, 78.29, 74.62, 74.25, 73.26, 53.76, 48.20, 33.52, 28.51,28.28, 25.88, 22.47, 22.27, 19.80, 12.82, 8.53, 8.43; ESIMS m/z 450([M+Na]⁺).

Example 6 Steps 1a and 2. Preparation of3-hydroxy-N-((3S,7R,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxy-1,5-dioxonan-3-yl)-4-methoxypicolinamide(53)

Step 1a

To a solution of tert-butyl((3S,7R,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxy-1,5-dioxonan-3-yl)carbamate(170 mg, 0.423 mmol) in DCM (3 mL) was added 4M HCl in dioxane (1058 μL,4.23 mmol) and the resulting solution was stirred at room temperaturefor 3 h. The solvent was evaporated under a stream of N₂ to give a whitesolid. This solid was triturated with Et₂O (3×3 mL) and the resultingpowder was dried under high vacuum for 1 h.(3S,7R,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxy-1,5-dioxonan-3-aminiumchloride: ESIMS m/z 302 ([M+H]⁺).

Step 2

To a solution of(3S,7R,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxy-1,5-dioxonan-3-aminiumchloride in DCM (3 mL) were added PyBop (242 mg, 0.466 mmol) and3-hydroxy-4-methoxypicolinic acid (79 mg, 0.466 mmol), followed by thedropwise addition of N-Ethyl-N-isopropylpropan-2-amine (243 μL, 1.40mmol). After 10 min, everything had solubilized and the solution wasstirred for 5 h. The resulting pink solution was treated with Celite® (2scoopula tip-fulls) and the solvent was removed under reduced pressure.The resulting adsorbed material was directly loaded onto a column andpurified using flash column chromatography (40 g SiO₂, 0→100%EtOAc/hexanes) to provide the title compound (136 mg, 0.301 mmol, 71%)as a sticky, white solid: mp 54-57° C.; IR (thin film): 3368, 2955,2873, 1746, 1648, 1528, 1263, 1087 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 11.99(s, 1H), 8.73 (d, J=8.1 Hz, 1H), 7.99 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.3Hz, 1H), 5.19-5.07 (m, 1H), 5.07-4.97 (m, 1H), 4.09-3.91 (m, 6H),3.68-3.52 (m, 2H), 3.29-3.19 (m, 1H), 3.08 (dd, J=9.8, 6.0 Hz, 1H),1.91-1.80 (m, 1H), 1.77-1.64 (m, 1H), 1.63-1.30 (m, 7H), 1.28-1.10 (m,2H), 0.97-0.86 (m, 9H); HRMS-ESI m/z [M+H)]⁺ calcd for: C₂₃H₃₇N₂O₇,453.2595; found, 453.2608.

Example 6 Steps 1b and 2. Preparation ofN-((3S,7R,8S,9S)-8-benzyl-7-((benzyloxy)methoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide(72)

Step 1b

To a solution of tert-butyl((3S,7R,8S,9S)-8-benzyl-7-((benzyloxy)methoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate(46.3 mg, 0.093 mmol) in DCM (0.93 mL) was added 2,6-dimethylpyridine(32.4 μl, 0.278 mmol), followed by the dropwise addition oftrimethylsilyl trifluoromethanesulfonate (33.5 μl, 0.185 mmol) at roomtemperature. The reaction was stirred at room temperature for 1.5 h,treated with MeOH (0.3 mL), and stirred overnight at room temperature.The solvent was then removed under a stream of N₂ to give(3S,7R,8S,9S)-8-benzyl-7-((benzyloxy)methoxy)-9-methyl-2-oxo-1,5-dioxonan-3-aminiumtrifluoromethanesulfonate: ESIMS m/z 400 ([M+H]⁺).

Step 2

To a solution of(3S,7R,8S,9S)-8-benzyl-7-((benzyloxy)methoxy)-9-methyl-2-oxo-1,5-dioxonan-3-aminiumtrifluoromethanesulfonate in DCM (0.93 mL) was added3-hydroxy-4-methoxypicolinic acid (17.24 mg, 0.102 mmol) followed byN-Ethyl-N-isopropylpropan-2-amine (53.3 μl, 0.306 mmol) and PyBop (53.1mg, 0.102 mmol), and the reaction was stirred at room temperatureovernight. The solvent was removed under a stream of N₂ and theresulting oil was purified by flash column chromatography (SiO₂, 1→40%acetone/hexanes) to afford the title compound (35.7 mg, 0.065 mmol, 70%)as a white foam: IR (thin film) 3369, 3028, 2938, 1744, 1649, 1577,1528, 1453 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 11.98 (d, J=0.7 Hz, 1H), 8.71(d, J=8.1 Hz, 1H), 8.00 (d, J=5.2 Hz, 1H), 7.38-7.21 (m, 9H), 7.23-7.17(m, 1H), 6.86 (d, J=5.2 Hz, 1H), 5.17 (dq, J=8.3, 6.4 Hz, 1H), 5.04(ddd, J=8.1, 6.4, 4.6 Hz, 1H), 4.85 (d, J=7.0 Hz, 1H), 4.73 (d, J=7.0Hz, 1H), 4.65 (d, J=11.9 Hz, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.19 (dd,J=11.7, 6.4 Hz, 1H), 3.98-3.94 (m, 1H), 3.93 (s, 3H), 3.87 (dd, J=11.8,5.5 Hz, 1H), 3.83 (dd, J=11.7, 4.7 Hz, 1H), 3.62 (ddd, J=8.8, 5.4, 2.0Hz, 1H), 3.00 (dd, J=14.7, 4.5 Hz, 1H), 2.69 (dd, J=14.7, 7.2 Hz, 1H),2.36 (tdd, J=8.5, 7.2, 4.5 Hz, 1H), 1.31 (d, J=6.4 Hz, 3H); HRMS-ESI m/z[M+H)]⁺ calcd for: C₃₀H₃₅N₂O₈, 551.2388; found, 551.2388.

Example 7 Preparation of((2-(((3S,7R,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxy-1,5-dioxonan-3-yl)carbamoyl)-4-methoxypyridin-3-yl)oxy)methylacetate (18)

To a solution of3-hydroxy-N-((3S,7R,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxy-1,5-dioxonan-3-yl)-4-methoxypicolinamide(105 mg, 0.232 mmol) and K₂CO₃ (64.1 mg, 0.464 mmol) in acetone (2.32mL) was added bromomethyl acetate (49.7 mg, 0.325 mmol), and thereaction was heated to 50° C. and stirred at this temperature for 4 h.The mixture was cooled to room temperature, diluted with DCM (4 mL), andtreated with Celite® (3 scoopula tip-fulls). The solvent was removedunder reduced pressure and the resulting adsorbed material was directlyloaded onto a column and purified using flash column chromatography (24g SiO₂, 0→100% EtOAc/hexanes) to afford the title compound (79 mg, 0.151mmol, 65%) as a slightly-yellow, viscous oil: IR (thin film): 3380,2955, 2873, 1749, 1676, 1503, 1200, 1086 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ8.60 (d, J=7.8 Hz, 1H), 8.29 (d, J=5.4 Hz, 1H), 6.96 (d, J=5.4 Hz, 1H),5.78-5.69 (m, 2H), 5.16-5.00 (m, 2H), 4.08-3.86 (m, 6H), 3.68-3.52 (m,2H), 3.31-3.15 (m, 1H), 3.07 (dd, J=9.9, 6.2 Hz, 1H), 2.07 (s, 3H),1.92-1.80 (m, 1H), 1.78-1.65 (m, 1H), 1.62-1.31 (m, 7H), 1.25-1.07 (m,2H), 0.96-0.85 (m, 9H); HRMS-ESI m/z [M+H)]⁺ calcd for: C₂₆H₄₁N₂O₉,525.2807; found, 525.2805.

Example 8 Preparation of(3S,7R,8S,9S)-3-(3-acetoxy-4-methoxypicolinamido)-8-isopentyl-9-methyl-2-oxo-1,5-dioxonan-7-ylcyclopropanecarboxylate (68)

To a solution of(3S,7R,8S,9S)-3-(3-hydroxy-4-methoxypicolinamido)-8-isopentyl-9-methyl-2-oxo-1,5-dioxonan-7-ylcyclopropanecarboxylate (96 mg, 0.201 mmol) and acetyl chloride (21.4μL, 0.301 mmol) in DCM (2.01 mL) was added TEA (41.9 μL, 0.301 mmol),and the reaction was stirred for 5 h. The mixture was treated withCelite® (3 scoopula tip-fulls) and the solvent was removed under reducedpressure. The adsorbed material was directly loaded onto a column andpurified using flash column chromatography (24 g SiO₂, 0→100%EtOAc/hexanes) to afford the title compound (86 mg, 0.165 mmol, 82%) asa white powder: mp: 70-75° C.; IR (thin film): 3376, 2954, 1771, 1725,1678, 1507, 1196, 1172 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.72 (d, J=8.4Hz, 1H), 8.34 (d, J=5.3 Hz, 1H), 7.01 (d, J=5.5 Hz, 1H), 5.13-5.00 (m,2H), 4.75 (ddd, J=10.1, 5.2, 2.7 Hz, 1H), 4.04 (dd, J=11.8, 6.8 Hz, 1H),3.90 (s, 3H), 3.81-3.72 (m, 3H), 2.38 (s, 3H), 2.16-2.04 (m, 1H),1.66-1.28 (m, 7H), 1.18-1.06 (m, 2H), 1.04-0.95 (m, 2H), 0.91-0.82 (m,8H); HRMS-ESI m/z [M+H)]⁺ calcd for: C₃₀H₃₅N₂O₈, 521.2494; found,521.2495.

Example 9 Preparation of((2-(((3S,7R,8S,9S)-8-(4-fluorobenzyl)-9-methyl-2-oxo-7-propoxy-1,5-dioxonan-3-yl)carbamoyl)-4-methoxypyridin-3-yl)oxy)methyl2-ethoxyacetate

To a solution ofN-((3S,7R,8S,9S)-8-(4-fluorobenzyl)-9-methyl-2-oxo-7-propoxy-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide(64.5 mg, 0.131 mmol), Na₂CO₃ (27.9 mg, 0.263 mmol), and NaI (3.94 mg,0.026 mmol) in acetone (1.3 mL) was added chloromethyl 2-ethoxyacetate(32.1 mg, 0.210 mmol), and the mixture was warmed to 55° C. and stirredat that temperature overnight. The solvent was evaporated under a streamof N₂ and the resulting oil was purified by flash column chromatography(SiO₂, 1→40% acetone/hexanes) to afford the title compound (64.6 mg,0.106 mmol, 81%) as a white foam: ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d,J=7.8 Hz, 1H), 8.28 (d, J=5.4 Hz, 1H), 7.18 (dd, J=8.5, 5.6 Hz, 2H),6.97 (t, J=8.7 Hz, 2H), 6.96 (d, J=5.5 Hz, 1H), 5.81 (s, 2H), 5.12 (dq,J=9.6, 6.3 Hz, 1H), 5.02 (ddd, J=7.8, 6.1, 3.8 Hz, 1H), 4.09 (s, 2H),4.06 (dd, J=11.7, 5.8 Hz, 1H), 4.00 (d, J=10.0 Hz, 1H), 3.96-3.91 (m,1H), 3.90 (s, 3H), 3.71 (dd, J=11.5, 5.8 Hz, 1H), 3.58 (q, J=7.0 Hz,2H), 3.55-3.52 (m, 1H), 3.25 (dt, J=9.0, 6.6 Hz, 1H), 3.08 (dd, J=10.3,5.1 Hz, 1H), 2.92 (dd, J=14.7, 4.1 Hz, 1H), 2.71 (dd, J=14.7, 6.0 Hz,1H), 2.22-2.10 (m, 1H), 1.65-1.50 (m, 2H), 1.32 (d, J=6.3 Hz, 3H), 1.22(t, J=7.0 Hz, 3H), 0.91 (t, J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ−117.38; HRMS-ESI m/z [M+H)]⁺ calcd for: C₃₀H₄₀FN₂O₁₀, 607.2662; found,607.2673.

Example A Evaluation of Fungicidal Activity: Leaf Blotch of Wheat(Mycosphaerella graminicola; Anamorph: Septoria tritici; Bayer CodeSEPTTR)

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of water containing 110 ppm Triton X-100. Thefungicide solutions were applied onto wheat seedlings using an automatedbooth sprayer to run-off. All sprayed plants were allowed to air dryprior to further handling. All fungicides were evaluated using theaforementioned method for their activity vs. all target diseases. Wheatleaf blotch and brown rust activity were also evaluated using trackspray applications, in which case the fungicides were formulated as ECformulations, containing 0.1% Trycol 5941 in the spray solutions.

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Septoria tritici either prior to or afterfungicide treatments. After inoculation the plants were kept in 100%relative humidity (one day in a dark dew chamber followed by two tothree days in a lighted dew chamber at 20° C.) to permit spores togerminate and infect the leaf. The plants were then transferred to agreenhouse set at 20° C. for disease to develop. When disease symptomswere fully expressed on the 1^(st) leaves of untreated plants, infectionlevels were assessed on a scale of 0 to 100 percent disease severity.Percent disease control was calculated using the ratio of diseaseseverity on treated plants relative to untreated plants.

Example B Evaluation of Fungicidal Activity: Wheat Brown Rust (PucciniaTriticina; Synonym: Puccinia Recondite f. sp. Tritici; Bayer CodePUCCRT)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Puccinia triticina either prior to orafter fungicide treatments. After inoculation the plants were kept in adark dew room at 22° C. with 100% relative humidity overnight to permitspores to germinate and infect the leaf. The plants were thentransferred to a greenhouse set at 24° C. for disease to develop.Fungicide formulation, application and disease assessment followed theprocedures as described in the Example A.

Example C Evaluation of Fungicidal Activity: Wheat Glume Blotch(Leptosphaeria nodorum; Bayer Code LEPTNO)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Leptosphaeria nodorum 24 hr afterfungicide treatments. After inoculation the plants were kept in 100%relative humidity (one day in a dark dew chamber followed by two days ina lighted dew chamber at 20° C.) to permit spores to germinate andinfect the leaf. The plants were then transferred to a greenhouse set at20° C. for disease to develop. Fungicide formulation, application anddisease assessment followed the procedures as described in the ExampleA.

Example D Evaluation of Fungicidal Activity: Apple Scab (Venturiainaequalis; Bayer Code VENTIN)

Apple seedlings (variety McIntosh) were grown in soil-less Metro mix,with one plant per pot. Seedlings with two expanding young leaves at thetop (older leaves at bottom of the plants were trimmed) were used in thetest. Plants were inoculated with a spore suspension of Venturiainaequalis 24 hr after fungicide treatment and kept in a 22° C. dewchamber with 100% RH for 48 hr, and then moved to a greenhouse set at20° C. for disease to develop. Fungicide formulation, application anddisease assessment on the sprayed leaves followed the procedures asdescribed in the Example A.

Example E Evaluation of Fungicidal Activity: Grape Powdery Mildew(Uncinula Necator; Bayer Code UNCINE)

Grape seedlings (variety Carignane) were grown in soil-less Metro mix,with one plant per pot, and used in the test when approximately onemonth old. Plants were inoculated 24 hr after fungicide treatment byshaking spores from infected leaves over test plants. Plants weremaintained in a greenhouse set at 20° C. until disease was fullydeveloped. Fungicide formulation, application and disease assessment onthe sprayed leaves followed the procedures as described in the ExampleA.

Example F Evaluation of Fungicidal Activity: Powdery Mildew of Cucumber(Erysiphe cichoracearum; Bayer Code ERYSCI)

Cucumber seedlings (variety Bush Pickle) were grown in soil-less Metromix, with one plant per pot, and used in the test when 12 to 14 daysold. Plants were inoculated with a spore suspension 24 hr followingfungicide treatments. After inoculation the plants remained in thegreenhouse set at 20° C. until disease was fully expressed. Fungicideformulation, application and disease assessment on the sprayed leavesfollowed the procedures as described in the Example A.

Example G Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets(Cercospora beticola; Bayer Code CERCBE)

Sugar beet plants (variety HH88) were grown in soil-less Metro mix andtrimmed regularly to maintain a uniform plant size prior to test. Plantswere inoculated with a spore suspension 24 hr after fungicidetreatments. Inoculated plants were kept in a dew chamber at 22° C. for48 hr then incubated in a greenhouse set at 24° C. under a clear plastichood with bottom ventilation until disease symptoms were fullyexpressed. Fungicide formulation, application and disease assessment onthe sprayed leaves followed the procedures as described in the ExampleA.

Example H Evaluation of Fungicidal Activity: Asian Soybean Rust(Phakopsora pachyrhizi; Bayer Code PHAKPA)

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of water containing 0.011% Tween 20. Thefungicide solutions were applied onto soybean seedlings using anautomated booth sprayer to run-off. All sprayed plants were allowed toair dry prior to further handling.

Soybean plants (variety Williams 82) were grown in soil-less Metro mix,with one plant per pot. Two weeks old seedlings were used for testing.Plants were inoculated either 3 days prior to or 1 day after fungicidetreatments. Plants were incubated for 24 h in a dark dew room at 22° C.and 100% RH then transferred to a growth room at 23° C. for disease todevelop. Disease severity was assessed on the sprayed leaves.

Example I Evaluation of Fungicidal Activity: Wheat Powdery Mildew(Blumeria graminis f. sp. Tritici; Synonym: Erysiphe graminis f. sp.Tritici; Bayer Code ERYSGT)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated bydusting with infected stock plants 24 hr after fungicide treatments.After inoculation the plants were kept in a greenhouse set at 20° C. fordisease to develop. Fungicide formulation, application and diseaseassessment on the sprayed leaves followed the procedures as described inthe Example A.

Example J Evaluation of Fungicidal Activity: Barley Powdery Mildew(Blumeria graminis f. sp. Hordei; Synonym: Erysiphe graminis f. sp.hordei; Bayer Code ERYSGH)

Barley seedlings (variety Harrington) were propagated in soil-less Metromix, with each pot having 8 to 12 plants, and used in the test whenfirst leaf was fully emerged. Test plants were inoculated by dustingwith infected stock plants 24 hr after fungicide treatments. Afterinoculation the plants were kept in a greenhouse set at 20° C. fordisease to develop. Fungicide formulation, application and diseaseassessment on the sprayed leaves followed the procedures as described inthe Example A.

Example K Evaluation of Fungicidal Activity: Barley Scald (Rhyncosporiumsecalis; Bayer Code RHYNSE)

Barley seedlings (variety Harrington) were propagated in soil-less Metromix, with each pot having 8 to 12 plants, and used in the test whenfirst leaf was fully emerged. Test plants were inoculated by an aqueousspore suspension of Rhyncosporium secalis 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 20°C. with 100% relative humidity for 48 hr. The plants were thentransferred to a greenhouse set at 20° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example L Evaluation of Fungicidal Activity: Rice Blast (Magnaporthegrisea; Anamorph: Pyricularia Oryzae; Bayer Code PYRIOR)

Rice seedlings (variety Japonica) were propagated in soil-less Metromix, with each pot having 8 to 14 plants, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Pyricularia oryzae 24 hr after fungicide treatments. Afterinoculation the plants were kept in a dew room at 22° C. with 100%relative humidity for 48 hr to permit spores to germinate and infect theleaf. The plants were then transferred to a greenhouse set at 24° C. fordisease to develop. Fungicide formulation, application and diseaseassessment on the sprayed leaves followed the procedures as described inthe Example A.

Example M Evaluation of Fungicidal Activity: Tomato Early Blight(Alternaria solani; Bayer Code ALTESO)

Tomato plants (variety Outdoor girl) were propagated in soil-less Metromix, with each pot having one plant, and used when 12 to 14 days old.Test plants were inoculated with an aqueous spore suspension ofAlternaria solani 24 hr after fungicide treatments. After inoculationthe plants were kept in 100% relative humidity (one day in a dark dewchamber followed by two to three days in a lighted dew chamber at 20°C.) to permit spores to germinate and infect the leaf. The plants werethen transferred to a growth room at 22° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example N Evaluation of Fungicidal Activity: Cucumber Anthracnose(Glomerella lagenarium; Anamorph: Colletotrichum lagenarium; Bayer CodeCOLLLA)

Cucumber seedlings (variety Bush Pickle) were propagated in soil-lessMetro mix, with each pot having one plant, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Colletotrichum lagenarium 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 22°C. with 100% relative humidity for 48 hr to permit spores to germinateand infect the leaf. The plants were then transferred to a growth roomset at 22° C. for disease to develop. Fungicide formulation, applicationand disease assessment on the sprayed leaves followed the procedures asdescribed in the Example A.

TABLE 1 Compound Structure and Appearance Prepared According Compound ToNumber Structure Example Appearance  1

Example 5, Step 1. Tacky Foam  2

Example 5, Step 1. Colorless Oil  3

Example 6, Step 2. White Solid  4

Example 1, Steps 1, 3-5; Example 2, Step 2; Example 3, Steps 1-4;Example 4. Pale Yellow Oil  5

Example 5, Step 2. Colorless Oil  6

Example 7. Colorless Oil  7

Example 1, Steps 1, 3-5; Example 2, Step 3; Example 3, Steps 1-4;Example 4. White Foam  8

Example 9. White Foam  9

Example 8. Yellow Foam 10

Example 8. White Foam 11

Example 6, Step 1a. White Powder 12

Example 1, Steps 1, 3, 6, 7, 8; Example 2, Step 1; Example 3, Steps 1-4;Example 4. Clear Oil 13

Example 6, Step 1a. White Solid 14

Example 7. Sticky Oil 15

Example 6, Step 1a. White Solid 16

Example 6, Step 1b. Colorless Oil 17

Example 6, Step 2. White Solid 18

Example 7. Viscous Oil 19

Example 6, Step 1a. White Solid 20

Example 8. White Foam 21

Example 1, Steps 1-5; Example 2, Step 3; Example 3, Steps 1-4; Example4. Colorless Oil 22

Example 1, Steps 1-5; Example 2, Step 1; Example 3, Steps 1-4; Example4. Colorless Oil 23

Example 6, Step 2. White Foam 24

Example 6, Step 2. White Foam 25

Example 6, Step 2. White Solid 26

Example 9. Colorless Oil 27

Example 5, Step 2. Colorless Oil 28

Example 8. White Foam 29

Example 1, Steps 1-5; Example 2, Step 2; Example 3, Steps 1-4; Example4. Colorless Oil 30

Example 7. White Foam 31

Example 6, Step 1a. White Solid 32

Example 7. Sticky White Solid 33

Example 6, Step 1a. White Solid 34

Example 6, Step 1a. White Solid 35

Example 6, Step 1a. White Powder 36

Example 6, Step 2. White Solid 37

Example 6, Step 2. White Solid 38

Example 6, Step 2. White Solid 39

Example 1, Steps 1-5; Example 2, Step 2; Example 3, Steps 1-4; Example4. White Solid 40

Example 7. Colorless Oil 41

Example 6, Step 1a. White Solid 42

Example 1, Steps 1-5; Example 2, Step 3; Example 3, Steps 1-4; Example4. White Solid 43

Example 7. Colorless Oil 44

Example 7. White Foam 45

Example 6, Step 2. White Foam 46

Example 6, Step 2. White Powder 47

Example 8. White Powder 48

Example 7. Colorless Oil 49

Example 5, Step 2. White Solid 50

Example 6, Step 1a. White Solid 51

Example 1, Steps 1-5; Example 2, Step 1; Example 3, Steps 1-4; Example4. Colorless Oil 52

Example 6, Step 1a. White Solid 53

Example 6, Step 2. Sticky White Solid 54

Example 1, Steps 1, 3-5; Example 2, Step 3; Example 3, Steps 1-4;Example 4. Pale Yellow Oil 55

Example 1, Steps 1-5; Example 2, Step 2; Example 3, Steps 1-4; Example4. Colorless Oil 56

Example 1, Steps 1, 3-5; Example 2, Step 1; Example 3, Steps 1-4;Example 4. White Foam 57

Example 7. White Powder 58

Example 6, Step 2. White Solid 59

Example 7. White Foam 60

Example 6, Step 2. White Powder 61

Example 6, Step 1a. Colorless Oil 62

Example 7. White Foam 63

Example 6, Step 1a. White Powder 64

Example 7. White Foam 65

Example 6, Step 2. White Solid 66

Example 5, Step 1. White Solid 67

Example 8. White Powder 68

Example 8. White Powder 69

Example 6, Step 1a. White Powder 70

Example 1, Steps 1, 3-5; Example 2, Step 2; Example 3, Steps 1-4;Example 4. Colorless Oil 71

Example 7. Pale Yellow Foam 72

Example 6, Step 2. Foam 73

Example 8. Clear Gel 74

Example 1, Steps 1, 3, 6, 7, 8; Example 2, Step 3; Example 3, Steps 1-4;Example 4. Clear Oil 75

Example 6, Step 1a. White Solid 76

Example 6, Step 2. Clear Gel 77

Example 6, Step 2. Pink Solid 78

Example 6, Step 1a. Tan Solid 79

Example 8. White Solid 80

Example 7. Yellow Gel 81

Example 8. White Solid 82

Example 1, Steps 1, 3, 6, 7, 8; Example 2, Step 2; Example 3, Steps 1-4;Example 4. Clear Oil 83

Example 6, Step 2. White Foam 84

Example 7. Yellow Gel 85

Example 7. Yellow Gel 86

Example 6, Step 1a. White Solid 87

Example 8. White Foam

TABLE 2 Analytical Data MP IR ¹³C or ¹⁹F Cmpd. No. (° C.) (cm⁻¹) MASS ¹HNMR NMR 1 — — ESIMS ¹H NMR (CDCl₃) δ 7.24- ¹⁹F NMR (CDCl₃) m/z 420 7.17(m, 2H), 6.96 (t, J = δ −116.84 ([M + Na]⁺) 8.7 Hz, 2H), 5.54 (d, J =8.3 Hz, 1H), 4.98 (dq, J = 9.0, 6.3 Hz, 1H), 4.70- 4.49 (m, 1H), 4.00(dd, J = 11.9, 6.6 Hz, 1H), 3.83- 3.72 (m, 2H), 3.61 (dd, J = 11.9, 5.3Hz, 1H), 3.55-3.42 (m, 1H), 2.94- 2.76 (m, 3H), 2.14 (tt, J = 9.1, 5.4Hz, 1H), 1.43 (s, 9H), 1.36 (d, J = 6.4 Hz, 3H) 2 — — ESIMS ¹H NMR(CDCl₃) δ 5.48 m/z 368 (d, J = 8.3 Hz, 1H), 5.03- ([M + Na]⁺) 4.90 (m,1H), 4.67-4.56 ¹³C NMR (CDCl₃) (m, 1H), 4.00 (dd, J = δ 171.68, 155.21,11.8, 6.7 Hz, 1H), 3.82- 80.16, 80.05, 3.70 (m, 2H), 3.60 (dd, J =74.03, 73.87, 11.8, 5.5 Hz, 1H), 3.56- 72.94, 53.59, 3.48 (m, 1H), 2.33(d, J = 50.52, 28.39, 6.2 Hz, 1H), 1.82 (tt, J = 28.27, 27.28, 9.1, 4.2Hz, 1H), 1.69- 23.28, 20.04, 13.93 1.58 (m, 1H), 1.44 (s, 9H), 1.39 (d,J = 6.4 Hz, 3H), 1.35-1.22 (m, 5H), 0.90 (t, J = 6.9 Hz, 3H) 3 — (ThinESIMS ¹H NMR (CDCl₃) δ 11.99 — Film) m/z 451 (d, J = 0.7 Hz, 1H), 8.733345, ([M + H]⁺) (d, J = 8.0 Hz, 1H), 8.00 2947, (d, J = 5.2 Hz, 1H),6.87 2868, (d, J = 5.2 Hz, 1H), 5.13 1741, (dq, J = 10.4, 6.3 Hz, 1H),1651  5.02 (ddd, J = 8.0, 6.2, 3.9 Hz, 1H), 4.09-3.95 (m, 2H), 3.96-3.90(m, 4H), 3.64 (dd, J = 11.2, 6.3 Hz, 1H), 3.43 (dd, J = 10.0, 6.9 Hz,1H), 3.17 (dd, J = 10.0, 6.8 Hz, 1H), 3.11 (ddd, J = 10.0, 6.4, 1.1 Hz,1H), 1.88 (tt, J = 10.1, 3.9 Hz, 1H), 1.73 (ddt, J = 12.5, 10.3, 4.1 Hz,1H), 1.40 (d, J = 6.3 Hz, 3H), 1.39-1.19 (m, 5H), 1.03 (dddd, J = 12.8,6.8, 5.0, 2.6 Hz, 1H), 0.97-0.87 (t, J = 6.9 Hz, 3H), 0.60- 0.47 (m,2H), 0.24-0.14 (m, 2H) 4 — — ESIMS ¹H NMR (CDCl₃) δ 7.20- ¹³C NMR(CDCl₃) m/z 462 7.12 (m, 2H), 7.00- δ 170.94, 161.34 ([M + Na]⁺) 6.89(m, 2H), 5.41-5.32 (d, J = 244.1 Hz), (m, 1H), 5.08 (dq, J = 9.6,155.21, 135.97 (d, 6.4 Hz, 1H), 4.66-4.52 J = 3.4 Hz), 130.49 (m, 1H),4.02-3.88 (m, (d, J = 7.8 Hz), 2H), 3.86-3.76 (m, 1H), 115.07 (d, J =21.0 3.64 (dd, J = 11.5, 5.7 Hz, Hz), 81.83, 80.00, 1H), 3.53 (dt, J =9.0, 6.6 79.09, 75.30, Hz, 1H), 3.23 (dt, J = 9.0, 73.70, 70.94, 6.6 Hz,1H), 3.02 (ddd, J = 54.48, 51.98, 9.7, 5.7, 1.4 Hz, 1H), 34.69, 28.28,2.91 (dd, J = 14.6, 4.1 Hz, 23.13, 20.70, 10.72 1H), 2.67 (dd, J = 14.7,6.1 Hz, 1H), 2.21-2.05 (m, 1H), 1.57 (p, J = 6.8 Hz, 2H), 1.43 (s, 9H),1.29 (d, J = 6.3 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H) 5 — — ESIMS ¹H NMR(CDCl₃) δ 7.15 ¹⁹F NMR (CDCl₃) m/z 488 (dd, J = 8.5, 5.5 Hz, 2H), δ−116.80 ([M + Na]⁺) 6.97 (t, J = 8.7 Hz, 2H), 5.42 (d, J = 8.2 Hz, 1H),5.16-5.01 (m, 1H), 4.72 (ddd, J = 9.4, 4.7, 2.6 Hz, 1H), 4.67 (ddd, J =8.2, 6.3, 4.5 Hz, 1H), 4.01 (dd, J = 11.6, 6.4 Hz, 1H), 3.83-3.73 (m,2H), 3.69 (dd, J = 11.6, 4.6 Hz, 1H), 2.76 (dd, J = 14.8, 6.3 Hz, 1H),2.65 (dd, J = 14.8, 5.6 Hz, 1H), 2.45 (td, J = 8.9, 4.4 Hz, 1H), 1.52-1.46 (m, 1H), 1.43 (s, 9H), 1.37 (d, J = 6.4 Hz, 3H), 0.98-0.92 (m, 2H),0.87-0.81 (m, 2H) 6 — (Thin HRMS-ESI ¹H NMR (CDCl₃) δ 8.59 — Film) (m/z)(d, J = 7.8 Hz, 1H), 8.29 3377, [M + H]⁺ (d, J = 5.4 Hz, 1H), 6.95 2934,calcd for (d, J = 5.4 Hz, 1H), 5.78- 2873, C₂₆H₃₈N₂O₉, 5.70 (m, 2H),5.15-5.01 1748, 523.2650; (m, 2H), 4.06-3.95 (m, 1676  found, 2H),3.93-3.86 (m, 4H), 523.2659 3.64 (dd, J = 11.1, 6.4 Hz, 1H), 3.42 (dd, J= 10.0, 6.9 Hz, 1H), 3.16 (dd, J = 10.0, 6.8 Hz, 1H), 3.10 (ddd, J =10.0, 6.5, 1.2 Hz, 1H), 2.07 (s, 3H), 1.93-1.82 (m, 1H), 1.79- 1.68 (m,1H), 1.39 (d, J = 6.3 Hz, 3H), 1.36-1.17 (m, 5H), 1.02 (dddd, J = 12.9,6.8, 5.0, 2.6 Hz, 1H), 0.90 (t, J = 6.9 Hz, 3H), 0.60-0.45 (m, 2H),0.24-0.13 (m, 2H) 7 — — ESIMS ¹H NMR (CDCl₃) δ 7.36- ¹⁹F NMR (CDCl₃) m/z510 7.22 (m, 5H), 7.11 (dd, δ −117.05 ([M + Na]⁺) J = 8.5, 5.5 Hz, 2H),6.91 (t, J = 8.7 Hz, 2H), 5.45 (d, J = 8.0 Hz, 1H), 5.11 (dt, J = 12.6,6.3 Hz, 1H), 4.63 (d, J = 11.5 Hz, 2H), 4.36 (d, J = 11.5 Hz, 1H), 4.10(d, J = 11.6 Hz, 1H), 3.97 (dd, J = 12.1, 5.9 Hz, 1H), 3.85 (dd, J =12.1, 3.5 Hz, 1H), 3.72 (dd, J = 11.7, 5.7 Hz, 1H), 3.21 (ddd, J = 9.6,5.7, 1.4 Hz, 1H), 2.89 (dd, J = 14.7, 4.3 Hz, 1H), 2.71 (dd, J = 14.7,6.0 Hz, 1H), 2.19 (dtd, J = 9.7, 6.5, 6.1, 3.6 Hz, 1H), 1.44 (s, 9H),1.31 (d, J = 6.4 Hz, 3H) 8 — — HRMS-ESI ¹H NMR (CDCl₃) δ 8.60 ¹⁹F NMR(CDCl₃) (m/z) (d, J = 7.8 Hz, 1H), 8.28 δ −117.38 [M + H]⁺ (d, J = 5.4Hz, 1H), 7.18 calcd for (dd, J = 8.5, 5.6 Hz, 2H), C₃₀H₄₀FN₂O₁₀, 6.97(t, J = 8.7 Hz, 2H), 607.2662; 6.96 (d, J = 5.5 Hz, 1H), found, 5.81 (s,2H), 5.12 (dq, J = 607.2673 9.6, 6.3 Hz, 1H), 5.02 (ddd, J = 7.8, 6.1,3.8 Hz, 1H), 4.09 (s, 2H), 4.06 (dd, J = 11.7, 5.8 Hz, 1H), 4.00 (d, J =10.0 Hz, 1H), 3.96-3.91 (m, 1H), 3.90 (s, 3H), 3.71 (dd, J = 11.5, 5.8Hz, 1H), 3.58 (q, J = 7.0 Hz, 2H), 3.55-3.52 (m, 1H), 3.25 (dt, J = 9.0,6.6 Hz, 1H), 3.08 (dd, J = 10.3, 5.1 Hz, 1H), 2.92 (dd, J = 14.7, 4.1Hz, 1H), 2.71 (dd, J = 14.7, 6.0 Hz, 1H), 2.22-2.10 (m, 1H), 1.65-1.50(m, 2H), 1.32 (d, J = 6.3 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H), 0.91 (t, J= 7.4 Hz, 3H) 9 — (Thin HRMS-ESI ¹H NMR (CDCl₃) δ 8.75 — Film) (m/z) (s,1H), 8.35 (d, J = 5.4 3376, [M + H]⁺ Hz, 1H), 7.00 (d, J = 5.5 2934,calcd for Hz, 1H), 5.14-4.98 (m, 2873, C₂₅H₃₆N₂O₈, 2H), 4.05-3.94 (m,2H), 1771, 493.2544; 3.91 (s, 3H), 3.86 (dd, J = 1745  found 12.0, 4.1Hz, 1H), 3.63 493.2557 (dd, J = 11.0, 6.5 Hz, 1H), 3.42 (dd, J = 10.0,6.9 Hz, 1H), 3.16 (dd, J = 10.0, 6.8 Hz, 1H), 3.10 (dd, J = 9.9, 6.3 Hz,1H), 2.39 (s, 3H), 1.92-1.81 (m, 1H), 1.80-1.67(m, 1H), 1.38 (d, J = 6.3Hz, 3H), 1.35- 1.18 (m, 5H), 1.08-0.97 (m, 1H), 0.95-0.84 (m, 3H),0.59-0.47 (m, 2H), 0.24-0.13 (m, 2H) 10 — — HRMS-ESI ¹H NMR (CDCl₃) δ8.79 ¹⁹F NMR (CDCl₃) (m/z) (d, J = 8.1 Hz, 1H), 8.35 δ −116.96 [M + H]⁺(d, J = 5.4 Hz, 1H), 7.12- calcd for 7.05 (m, 4H), 7.00 (d, J =C₃₁H₃₄FN₂O₈, 5.5 Hz, 1H), 6.91 (t, J = 581.2294; 8.7 Hz, 2H), 6.74 (d, J= found, 8.5 Hz, 2H), 5.20 (dq, J = 581.2303 10.1, 6.2 Hz, 1H), 5.06(ddd, J = 8.1, 6.1, 3.5 Hz, 1H), 4.06-3.93 (m, 3H), 3.95-3.87 (m, 1H),3.89 (s, 3H), 3.73 (dd, J = 11.2, 6.2 Hz, 1H), 2.95 (dd, J = 14.7, 4.9Hz, 1H), 2.83 (dd, J = 14.7, 4.3 Hz, 1H), 2.44-2.38 (m, 1H), 2.38 (s,3H), 2.28 (s, 3H), 1.48 (d, J = 6.3 Hz, 3H) 11 — — ESIMS — — m/z 302([M + H]⁺) 12 — — ESIMS ¹H NMR (CDCl₃) δ 7.32- — m/z 478.4 7.10 (m, 7H),6.96 (t, J = ([M + Na]⁺) 7.4 Hz, 1H), 6.83 (d, J = 9.7 Hz, 2H), 5.39 (d,J = 7.9 Hz, 1H), 5.26-5.12 (m, 1H), 4.71-4.59 (m, 1H), 4.07-3.82 (m,4H), 3.72 (dd, J = 11.4, 6.1 Hz, 1H), 2.95-2.85 (m, 2H), 2.51-2.33 (m,1H), 1.46 (d, J = 6.4 Hz, 3H), 1.44 (s, 9H) 13 — — ESIMS ¹H NMR (CDCl₃)δ 8.70 ¹³C NMR (CDCl₃) m/z 300 (bs, 3H), 5.06 (dq, J = δ 168.36, 80.25,([M + H]⁺) 12.2, 6.2 Hz, 1H), 4.60 79.95, 74.80, (dd, J = 5.8, 3.2 Hz,1H), 74.29, 71.11, 4.34 (d, J = 13.3 Hz, 1H), 53.89, 49.92, 4.13-3.90(m, 2H), 3.56 27.99, 27.09, (dd, J = 11.3, 6.1 Hz, 1H), 23.33, 19.78,3.42 (dd, J = 10.1, 6.8 Hz, 13.94, 10.70, 2.96 1H), 3.16 (dd, J = 10.0,6.8 Hz, 1H), 3.09 (dd, J = 10.0, 6.0 Hz, 1H), 1.90- 1.78 (m, 1H),1.76-1.62 (m, 1H), 1.39 (d, J = 6.2 Hz, 3H), 1.35-1.19 (m, 5H),1.07-0.96 (m, 1H), 0.91 (t, J = 6.8 Hz, 3H), 0.51 (d, J = 8.0 Hz, 2H),0.25-0.13 (m, 2H) 14 — (Thin HRMS-ESI ¹H NMR (CDCl₃) δ 8.62 — Film)(m/z) (d, J = 7.8 Hz, 1H), 8.30 3378, [M + H]⁺ (d, J = 5.4 Hz, 1H),7.38- 2952, calcd for 7.25 (m, 5H), 6.96 (d, J = 2871, C₃₀H₄₁N₂O₉, 5.4Hz, 1H), 5.78-5.70 1748, 573.2807; (m, 2H), 5.18-5.02 (m, 1676, found,2H), 4.65 (d, J = 11.2 Hz, 1502, 573.2823 1H), 4.38 (d, J = 11.2 Hz,1200  1H), 4.15-4.02 (m, 2H), 3.98-3.88 (m, 4H), 3.73 (dd, J = 11.2, 6.3Hz, 1H), 3.28 (dd, J = 9.9, 6.0 Hz, 1H), 2.07 (s, 3H), 1.99- 1.86 (m,1H), 1.80-1.66 (m, 1H), 1.47-1.29 (m, 5H), 1.20-1.00 (m, 2H), 0.84 (appt, J = 7.1 Hz, 6H) 15 — — ESIMS — — m/z 366 ([M + H]⁺) 16 — — ESIMS — —m/z 400 ([M + H]⁺) 17 — — HRMS-ESI ¹H NMR (CDCl₃) δ 11.97 ¹⁹F NMR(CDCl₃) (m/z) (d, J = 0.6 Hz, 1H), 8.72 δ −117.30 ([M + H]⁺) (d, J = 8.0Hz, 1H), 8.01 calcd for (d, J = 5.2 Hz, 1H), 7.23- C₂₅H₃₂FN₂O₇, 7.13 (m,2H), 6.97 (t, J = 491.2188; 8.7 Hz, 2H), 6.87 (d, J = found, 5.4 Hz,1H), 5.15 (dq, J = 491.2198 9.5, 6.3 Hz, 1H), 5.01 (ddd, J = 8.0, 6.0,3.6 Hz, 1H), 4.08 (dd, J = 12.1, 6.0 Hz, 1H), 4.02 (d, J = 11.2 Hz, 1H),3.96 (dd, J = 12.1, 3.6 Hz, 1H), 3.94 (s, 3H), 3.71 (dd, J = 11.6, 5.7Hz, 1H), 3.55 (dt, J = 9.0, 6.7 Hz, 1H), 3.26 (dt, J = 8.9, 6.6 Hz, 1H),3.09 (ddd, J = 9.8, 5.6, 1.3 Hz, 1H), 2.93 (dd, J = 14.7, 4.2 Hz, 1H),2.71 (dd, J = 14.6, 6.1 Hz, 1H), 2.23- 2.09 (m, 1H), 1.67-1.50 (m, 2H),1.33 (d, J = 6.3 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H) 18 — (Thin HRMS-ESI¹H NMR (CDCl₃) δ 8.60 — Film) (m/z) (d, J = 7.8 Hz, 1H), 8.29 3380,([M + H]⁺) (d, J = 5.4 Hz, 1H), 6.96 2955, calcd for (d, J = 5.4 Hz,1H), 5.78- 2873, C₂₆H₄₁N₂O₉, 5.69 (m, 2H), 5.16-5.00 1749, 525.2807; (m,2H), 4.08-3.86 (m, 1676, found, 6H), 3.68-3.52 (m, 2H), 1503, 525.28053.31-3.15 (m, 1H), 3.07 1200, (dd, J = 9.9, 6.2 Hz, 1H), 1086  2.07 (s,3H), 1.92-1.80 (m, 1H), 1.78-1.65 (m, 1H), 1.62-1.31 (m, 7H) 1.25-1.07(m, 2H), 0.96- 0.85 (m, 9H) 19 — — ESIMS — — m/z 352 ([M + H]⁺) 20 — —HRMS-ESI ¹H NMR (CDCl₃) δ 8.76 ¹⁹F NMR (CDCl₃) (m/z) (d, J = 7.9 Hz,1H), 8.33 δ −117.35 [M + H]⁺ (d, J = 5.4 Hz, 1H), 7.18 calcd for (dd, J= 8.5, 5.6 Hz, 2H), C₂₇H₃₄FN₂O₈ 7.00 (d, J = 5.5 Hz, 1H), 533.2294; 6.96(t, J = 8.7 Hz, 2H), found, 5.11 (dq, J = 9.6, 6.3 Hz, 533.2307 1H),5.01 (ddd, J = 8.0, 6.1, 3.8 Hz, 1H), 4.04 (dd, J = 12.2, 6.3 Hz, 1H),4.00 (d, J = 11.5 Hz, 1H), 3.94-3.85 (m, 1H), 3.89 (s, 3H), 3.69 (dd, J= 11.4, 5.8 Hz, 1H), 3.55 (dt, J = 8.9, 6.6 Hz, 1H), 3.25 (dt, J = 8.9,6.6 Hz, 1H), 3.07 (ddd, J = 9.8, 5.9, 1.4 Hz, 1H), 2.91 (dd, J = 14.7,4.0 Hz, 1H), 2.70 (dd, J = 14.7, 6.0 Hz, 1H), 2.38 (s, 3H), 2.15 (tdd, J= 9.8, 6.1, 4.1 Hz, 1H), 1.64- 1.50 (m, 2H), 1.31 (d, J = 6.3 Hz, 3H),0.91 (t, J = 7.4 Hz, 3H) 21 — — ESIMS ¹H NMR (CDCl₃) δ 7.39- ¹³C NMR(CDCl₃) m/z 458 7.27 (m, 5H), 5.35 (d, J = δ 171.19, 155.22, ([M + Na]⁺)8.0 Hz, 1H), 5.07 (dq, J = 137.86, 128.39, 12.2, 6.3 Hz, 1H), 4.69-127.90, 127.74, 4.59 (m, 2H), 4.36 (d, J = 80.71, 80.06, 11.3 Hz, 1H),4.11- 79.43, 75.31, 4.03 (m, 1H), 3.95 (dd, J = 73.62, 71.51, 12.0, 6.1Hz, 1H), 3.86- 54.36, 49.97, 3.78 (m, 1H), 3.66 (dd, 28.31, 28.02, J =11.3, 6.2 Hz, 1H), 26.95, 23.39, 3.21 (ddd, J = 9.9, 6.2, 1.2 19.93,13.97 Hz, 1H), 1.88 (tt, J = 10.1, 3.9 Hz, 1H), 1.74-1.56 (m, 2H), 1.44(s, 9H), 1.37 (d, J = 6.3 Hz, 3H), 1.29-1.17 (m, 3H), 1.17- 1.05 (m,1H), 0.85 (t, J = 7.0 Hz, 3H) 22 — — ESIMS ¹H NMR (CDCl₃) δ 7.32- ¹³CNMR (CDCl₃) m/z 444 7.25 (m, 2H), 6.94 (tt, J = δ 170.94, 157.21, ([M +Na]⁺) 7.4, 1.1 Hz, 1H), 6.90- 155.27, 129.65, 6.85 (m, 2H), 5.45 (d, J =120.89, 115.09, 8.0 Hz, 1H), 5.19 (dq, J = 80.18, 80.09, 10.4, 6.3 Hz,1H), 4.68 78.41, 75.86, (dt, J = 8.6, 4.5 Hz, 1H), 73.27, 54.68,4.06-3.97 (m, 2H), 3.90 50.18, 28.32, (d, J = 5.1 Hz, 2H), 3.66 28.04,27.02, (dd, J = 11.3, 6.2 Hz, 1H), 23.16, 19.92, 13.83 2.09 (tt, J =10.3, 3.9 Hz, 1H), 1.80-1.67 (m, 1H), 1.45 (s, 9H), 1.42 (d, J = 6.3 Hz,3H), 1.35-1.10 (m, 5H), 0.81 (t, J = 7.1 Hz, 3H) 23 — — HRMS-ESI ¹H NMR(CDCl₃) δ 11.97 ¹⁹F NMR (CDCl₃) (m/z) (s, 1H), 8.76 (d, J = 8.0 δ−116.88 [M + H]⁺ Hz, 1H), 8.02 (d, J = 5.2 calcd for Hz, 1H), 7.14-7.05(m, C₂₉H3₂FN₂O₇, 4H), 6.91 (t, J = 8.7 Hz, 539.2188; 2H), 6.88 (d, J =5.2 Hz, found, 1H), 6.74 (d, J = 8.5 Hz, 539.2194 2H), 5.25 (dq, J =10.0, 6.3 Hz, 1H), 5.06 (dt, J = 8.0, 4.6 Hz, 1H), 4.07 (d, J = 11.3 Hz,1H), 4.02 (d, J = 4.6 Hz, 2H), 4.00- 3.96 (m, 1H), 3.94 (s, 3H), 3.74(dd, J = 11.4, 6.0 Hz, 1H), 2.97 (dd, J = 14.7, 4.9 Hz, 1H), 2.84 (dd, J= 14.7, 4.3 Hz, 1H), 2.41 (tt, J = 9.8, 4.6 Hz, 1H), 2.29 (s, 3H), 1.50(d, J = 6.3 Hz, 3H) 24 — — HRMS-ESI ¹H NMR (CDCl₃) δ 11.97 ¹⁹F NMR(CDCl₃) (m/z) (s, 1H), 8.72 (d, J = 8.0 δ −117.23 [M + H]⁺ Hz, 1H),8.05-7.93 (m, calcd for 1H), 7.21 (dd, J = 8.4, 5.5 C₂₆H₃₂FN₂O₇, Hz,2H), 7.03-6.92 (m, 503.2188; 2H), 6.91-6.82 (m, 1H), found, 5.23-5.10(m, 1H), 5.01 503.2214 (ddd, J = 7.7, 6.0, 3.5 Hz, 1H), 4.11-3.96 (m,3H), 3.94 (s, 3H), 3.71 (dd, J = 11.6, 5.7 Hz, 1H), 3.36 (dd, J-10.157.1 Hz, 1H), 3.24 (dd, J = 10.1, 6.6 Hz, 1H), 3.12 (dd, J = 9.7, 5.6Hz, 1H), 2.95 (dd, J = 14.7, 4.1 Hz, 1H), 2.74 (dd, J = 14.7, 5.9 Hz,1H), 2.18 (tdd, J = 9.8, 5.9, 4.1 Hz, 1H), 1.34 (d, J = 6.3 Hz, 3H),1.10-0.98 (m, 1H), 0.59-0.49 (m, 2H), 0.26-0.18 (m, 2H) 25 — — HRMS-ESI¹H NMR (CDCl₃) δ 11.95 ¹⁹F NMR (CDCl₃) (m/z) (s, 1H), 8.72 (d, J = 8.1 δ−116.75 [M + H]⁺ Hz, 1H), 7.99 (d, J = 5.2 calcd for Hz, 1H), 7.17 (dd,J = 8.5, C₂₆H₃₀FN₂O₈, 5.5 Hz, 2H), 6.98 (t, J = 517.1986; 8.7 Hz, 2H),6.87 (d, J = found, 5.2 Hz, 1H), 5.16 (dq, J = 517.1981 8.1, 6.4 Hz,1H), 5.07 (ddd, J = 8.1, 6.3, 4.4 Hz, 1H), 4.78 (ddd, J = 9.2, 4.5, 2.7Hz, 1H), 4.16 (dd, J = 11.6, 6.4 Hz, 1H), 3.93 (s, 3H), 3.88-3.81 (m,3H), 2.80 (dd, J = 14.7, 6.5 Hz, 1H), 2.68 (dd, J = 14.8, 5.5 Hz, 1H),2.55-2.44 (m, 1H), 1.51 (tt, J = 8.0, 4.6 Hz, 1H), 1.40 (d, J = 6.4 Hz,3H), 1.00-0.94 (m, J = 2.5, 1.9 Hz, 2H), 0.89-0.84 (m, 2H) 26 — (ThinHRMS-ESI ¹H NMR (CDCl₃) δ 8.58 — Film) (m/z) (d, J = 7.9 Hz, 1H), 8.293375, [M + H]⁺ (d, J = 5.4 Hz, 1H), 7.36- 2919, calcd for 7.15 (m, 10H),6.95 (d, J = 1746, C₃₅H₄₃N₂O₁₁, 5.4 Hz, 1H), 5.81 (s, 1677, 667.2861;2H), 5.14 (dq, J = 8.3, 6.4 1505  found, Hz, 1H), 5.06 (ddd, J =667.2875 8.0, 6.5, 4.8 Hz, 1H), 4.85 (d, J = 7.1 Hz, 1H), 4.72 (d, J =7.0 Hz, 1H), 4.67- 4.56 (m, 2H), 4.17 (dd, J = 11.7, 6.6 Hz, 1H), 4.09(s, 2H), 3.96-3.91 (m, 1H), 3.91 (s, 3H), 3.87 (dd, J = 11.6, 5.5 Hz,1H), 3.82-3.75 (m, 1H), 3.66- 3.52 (m, 3H), 3.01 (dd, J = 14.7, 4.4 Hz,1H), 2.68 (dd, J = 14.7, 7.2 Hz, 1H), 2.41-2.27 (m, 1H), 1.31 (d, J =6.4 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H) 27 — — ESIMS ¹H NMR (CDCl₃) δ 5.33¹³C NMR (CDCl₃) m/z 438 (d, J = 8.3 Hz, 1H), 5.05 δ 175.82, 171.25,([M + Na]⁺) (dq, J = 10.1, 6.3 Hz, 1H), 155.16, 80.04, 4.74-4.61 (m,2H), 3.93 78.40, 74.45, (dd, J = 11.9, 6.6 Hz, 1H), 74.25, 73.28, 3.69(m, 3H), 2.54 (p, J = 53.76, 48.15, 7.0 Hz, 1H), 2.06 (ddt, J = 34.09,28.27, 9.9, 6.0, 4.0 Hz, 1H), 1.46 27.95, 26.78, (d, J = 5.8 Hz, 1H),1.43 23.24, 19.84, (s, 9H), 1.39 (d, J = 6.3 18.93, 13.84 Hz, 3H),1.37-1.26 (m, 1H), 1.25-1.19 (m, 4H), 1.16 (dd, J = 7.0, 2.0 Hz, 6H),0.87 (t, J = 6.9 Hz, 3H) 28 — (Thin HRMS-ESI ¹H NMR (CDCl₃) δ 8.55 —Film) (m/z) (d, J = 7.8 Hz, 1H), 8.14 3377, [M + H]⁺ (d, J = 5.4 Hz,1H), 7.02 2938, calcd for (dd, J = 8.5, 5.6 Hz, 2H), 2878, C₂₈H₃₄FN₂O₈,6.84-6.72 (m, 3H), 4.93 1770, 545.2294; (dq, J = 9.6, 6.3 Hz, 1H), 1745,found, 4.82 (ddd, J = 8.0, 6.1, 3.7 1508  545.2325 Hz, 1H), 3.84 (dd, J= 11.4, 5.5 Hz, 1H), 3.80 (d, J = 11.2 Hz, 1H), 3.74- 3.65 (m, 1H), 3.70(s, 3H), 3.50 (dd, J = 11.4, 5.9 Hz, 1H), 3.17 (dd, J = 10.1, 7.0 Hz,1H), 3.04 (dd, J = 10.1, 6.6 Hz, 1H), 2.92 (ddd, J = 9.5, 6.0, 1.4 Hz,1H), 2.75 (dd, J = 14.7, 4.1 Hz, 1H), 2.53 (dd, J = 14.6, 5.9 Hz, 1H),2.19 (s, 3H), 2.04-1.91 (m, 1H), 1.13 (d, J = 6.3 Hz, 3H), 0.88-0.78 (m,1H), 0.37-0.26 (m, 2H), 0.10-−0.10 (m, 2H) 29 — — ESIMS ¹H NMR (CDCl₃) δ5.35 ¹³C NMR (CDCl₃) m/z 478 (d, J = 7.9 Hz, 1H), 5.07 δ 171.08, 155.22,([M + Na]⁺) (dq, J = 10.3, 6.3 Hz, 1H), 127.16 (q, J = 4.61 (ddd, J =8.3, 6.0, 3.6 276.1 Hz), 81.58, Hz, 1H), 3.91 (dd, J = 80.04, 79.75,12.0, 6.1 Hz, 2H), 3.81 75.54, 73.50, (dd, J = 12.0, 3.7 Hz, 1H), 67.49,54.44, 3.66 (dt, J = 9.2, 5.8 Hz, 50.05, 30.83 (q, 1H), 3.63-3.53 (m,1H), J = 29.0 Hz), 3.29 (dt, J = 9.1, 6.2 Hz, 28.28, 28.12, 1H),3.08-2.97 (m, 1H), 27.32, 23.33, 22.73 2.27-2.07 (m, 2H), 1.80 (q, J =3.1 Hz), (qt, J = 8.0, 4.8 Hz, 3H), 19.85, 13.92 1.60 (tq, J = 10.4, 3.7Hz, 1H), 1.44 (s, 9H), 1.37 (d, J = 6.2 Hz, 3H), 1.35- 1.21 (m, 4H),1.22-1.10 (m, 1H), 0.89 (t, J = 7.1 Hz, 3H) 30 — — HRMS-ESI ¹H NMR(CDCl₃) δ 8.62 ¹⁹FNMR (CDCl₃) (m/z) (d, J = 7.7 Hz, 1H), 8.29 δ −117.21[M + H]⁺ (d, J = 5.3 Hz, 1H), 7.36- calcd for 7.25 (m, 5H), 7.13 (dd, J= C₃₂H₃₆FN₂O₉, 8.5, 5.6 Hz, 2H), 6.98- 611.2399; 6.88 (m, 3H), 5.79-5.65found, (m, 2H), 5.17 (dq, J = 9.5, 611.2398 6.3 Hz, 1H), 5.06 (ddd, J =7.8, 6.0, 3.6 Hz, 1H), 4.65 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.5 Hz,1H), 4.13 (d, J = 10.3 Hz, 1H), 4.10 (dd, J-11.0, 4.9 Hz, 1H), 3.97 (dd,J = 12.1, 3.6 Hz, 1H), 3.90 (s, 3H), 3.79 (dd, J = 11.6, 5.7 Hz, 1H),3.27 (ddd, J = 9.7, 5.7, 1.4 Hz, 1H), 2.91 (dd, J = 14.7, 4.2 Hz, 1H),2.75 (dd, J = 14.7, 6.0 Hz, 1H), 2.24 (tdd, J = 9.7, 6.0, 4.3 Hz, 1H),2.06 (s, 3H), 1.34 (d, J = 6.3 Hz, 3H) 31 — — ESIMS — — m/z 340 [M + H]⁺32 44-50 — HRMS-ESI ¹H NMR (CDCl₃) δ 8.67 — (m/z) (d, J = 7.8 Hz, 1H),8.32 [M + H]⁺ (d, J = 5.4 Hz, 1H), 7.32- calcd for 7.23 (m, 2H),7.00-6.86 C₂₉H₃₉N₂O₉, (m, 4H), 5.75 (s, 2H), 559.2650; 5.25 (dq, J =12.3, 6.3 Hz, found, 1H), 5.15-5.06 (m, 1H), 559.2673 4.11-4.00 (m, 4H),3.92 (s, 3H), 3.72 (dd, J = 11.3, 6.2 Hz, 1H), 2.20-2.05 (m, 4H),1.85-1.73 (m, 1H), 1.48-1.33 (m, 5H), 1.30-1.15 (m, 1H), 1.10- 0.97 (m,1H), 0.82 (d, J = 6.6 Hz, 3H), 0.77 (d, J = 6.6 Hz, 3H) 33 — — ESIMS — —m/z 356 [M + H]⁺ 34 — — ESIMS ¹H NMR (CDCl₃) δ 8.74 — m/z 316 (bs, 3H),5.19-5.10 (m, [M + H]⁺ 1H), 4.66-4.58 (m, 2H), 4.43 (dd, J = 13.0, 3.3Hz, 1H), 4.08 (dd, J = 13.1, 6.3 Hz, 1H), 3.85 (d, J = 11.2 Hz, 1H),3.70-3.62 (m, 1H), 2.53 (p, J = 7.0 Hz, 1H), 2.07 (dq, J = 10.1, 5.8,4.9 Hz, 1H), 1.45 (d, J = 5.2 Hz, 1H), 1.41 (d, J = 6.3 Hz, 3H),1.38-1.18 (m, 5H), 1.15 (dd, J = 7.0, 0.9 Hz, 6H), 0.90-0.83 (m, 3H) 35— — ESIMS — — m/z 328 [M + H]⁺ 36 80-82 — HRMS-ESI ¹H NMR (CDCl₃) δ11.95 — (m/z) (s, 1H), 8.69 (d, J = 8.3 [M + H]⁺ Hz, 1H), 8.00 (d, J =5.2 calcd for Hz, 1H), 6.88 (d, J = 5.2 C₂₄H₃₅N₂O₈, Hz, 1H), 5.17-5.01(m, 479.2388; 2H), 4.76 (ddd, J = 10.0, found, 5.6, 2.2 Hz, 1H), 4.08(dd, 479.2385 J = 11.9, 6.7 Hz, 1H), 3.94 (s, 3H), 3.88-3.72 (m, 3H),2.19-2.07 (m, 1H), 1.67-1.29 (m, 7H), 1.19-1.06 (m, 2H), 1.05- 0.96 (m,2H), 0.93- 0.83 (m, 8H) 37 — (Thin HRMS-ESI ¹H NMR (CDCl₃) δ 12.00 —Film) (m/z) (d, J = 0.6 Hz, 1H), 8.75 3377, [M + H]⁺ (d, J = 8.1 Hz,1H), 8.02 2936, calcd for (d, J = 5.2 Hz, 1H), 7.41- 2871, C₂₆H₃₄N₂O₇,7.23 (m, 5H), 6.87 (dd, J = 1731, 487.2439; 5.3, 0.6 Hz, 1H), 5.14 1641 found, (dq, J = 10.3, 6.3 Hz, 1H), 487.2413 5.04 (ddd, J = 8.0, 6.1, 3.8Hz, 1H), 4.65 (d, J = 11.3 Hz, 1H), 4.39 (d, J = 11.3 Hz, 1H), 4.12 (dd,J = 11.5, 1.0 Hz, 1H), 4.06 (d, J = 6.2 Hz, 1H), 3.98 (d, J = 3.9 Hz,1H), 3.94 (s, 3H), 3.72 (dd, J = 11.3, 6.1 Hz, 1H), 3.28 (ddd, J = 10.0,6.1, 1.1 Hz, 1H), 2.01-1.86 (m, 1H), 1.77- 1.64 (m, 1H), 1.40 (d, J =6.3 Hz, 3H), 1.38-1.29 (m, 1H), 1.28-1.19 (m, 3H), 1.19-1.07 (m, 1H),0.86 (t, J = 7.0 Hz, 3H) 38 — — HRMS-ESI ¹H NMR (CDCl₃) δ 11.99 ¹⁹F NMR(CDCl₃) (m/z) (d, J = 0.6 Hz, 1H), 8.75 δ −117.10 [M + H]⁺ (d, J = 8.0Hz, 1H), 8.00 calcd for (d, J = 5.2 Hz, 1H), 7.37- C₂₉H₃₂FN₂O₇, 7.26 (m,5H), 7.13 (dd, J = 539.2188; 8.6, 5.5 Hz, 2H), 6.93 (t, found, J = 8.7Hz, 2H), 6.86 (d, J = 539.2186 5.5 Hz, 1H), 5.19 (dq, J = 9.3, 6.3 Hz,1H), 5.03 (ddd, J-8.0, 5.9, 3.4 Hz, 1H), 4.65 (d, J = 11.5 Hz, 1H), 4.40(d, J = 11.5 Hz, 1H), 4.14 (d, J = 10.8 Hz, 1H), 4.11 (dd, J = 11.6, 5.4Hz, 1H), 4.00 (dd, J = 12.1, 3.4 Hz, 1H), 3.92 (s, 3H), 3.79 (dd, J =11.7, 5.6 Hz, 1H), 3.28 (ddd, J = 9.6, 5.5, 1.4 Hz, 1H), 2.91 (dd, J =14.7, 4.3 Hz, 1H), 2.75 (dd, J = 14.6, 6.0 Hz, 1H), 2.24 (tdd, J = 9.4,6.0, 4.3 Hz, 1H), 1.35 (d, J = 6.3 Hz, 3H) 39 74-77 — ESIMS ¹H NMR(CDCl₃) δ 5.35 — m/z 424 (d, J = 8.4 Hz, 1H), 5.11- ([M + Na]⁺) 4.99 (m,1H), 4.66-4.57 (m, 1H), 3.98-3.86 (m, 2H), 3.83-3.74 (m, 1H), 3.61-3.50(m, 2H), 3.26- 3.16 (m, 1H), 3.06- 2.97 (m, 1H), 1.87-1.74 (m, 1H),1.75-1.61 (m, 1H), 1.62-1.39 (m, 12H), 1.41-1.27 (m, 4H), 1.23-1.07 (m,2H), 0.95-0.85 (m, 9H) 40 — (Thin HRMS-ESI ¹H NMR (CDCl₃) δ 8.62 — Film)(m/z) (d, J = 7.8 Hz, 1H), 8.30 3380, [M + H]⁺ (d, J = 5.4 Hz, 1H),7.39- 2953 calcd for 7.27 (m, 5H), 6.96 (d, J = 2872, C₂₉H₃₈N₂O₉, 5.4Hz, 1H), 5.74 (d, J = 1748, 559.2650; 1.7 Hz, 2H), 5.18-5.02 1676 found, (m, 2H), 4.65 (d, J = 11.3 559.2651 Hz, 1H), 4.38 (d, J = 11.3Hz, 1H), 4.14-4.01 (m, 2H), 3.97-3.92 (m, 1H), 3.91 (s, 3H), 3.72 (dd, J= 11.3, 6.2 Hz, 1H), 3.28 (ddd, J = 10.1, 6.3, 1.2 Hz, 1H), 2.07 (s,3H), 1.91 (tt, J = 10.1, 3.9 Hz, 1H), 1.77-1.62 (m, 1H), 1.39 (d, J =6.3 Hz, 3H), 1.37-1.30(m, 1H), 1.30- 1.18 (m, 3H), 1.17- 1.05 (m, 1H),0.85 (t, J = 7.0 Hz, 3H) 41 — — ESIMS — — m/z 388 ([M + H]⁺) 42 70-72 —ESIMS ¹H NMR (CDCl₃) δ 7.38- — m/z 472 7.24 (m, 5H), 5.35 (d, J = ([M +Na]⁺) 8.2 Hz, 1H), 5.07 (dq, J = 12.3, 6.3 Hz, 1H), 4.68- 4.59 (m, 2H),4.36 (d, J = 11.2 Hz, 1H), 4.07 (d, J = 11.3 Hz, 1H), 3.95 (dd, J =12.0, 6.2 Hz, 1H), 3.81 (dd, J = 11.9, 3.9 Hz, 1H), 3.66 (dd, J = 11.3,6.2 Hz, 1H), 3.22 (dd, J = 9.9, 6.2 Hz, 1H), 1.95- 1.83 (m, 1H),1.77-1.63 (m, 1H), 1.48-1.27 (m, 14H), 1.19-0.99 (m, 2H), 0.83 (app dd,J = 7.6, 6.6 Hz, 6H) 43 — (Thin HRMS-ESI ¹H NMR (CDCl₃) δ 8.56 — Film)(m/z) (d, J = 8.0 Hz, 1H), 8.29 3376, [M + H]⁺ (d, J = 5.3 Hz, 1H), 6.962956, calcd for (d, J = 5.4 Hz, 1H), 5.73 2875, C₂₆H₃₈N₂O₄, (d, J = 0.8Hz, 2H), 5.16- 1733, 539.2599; 5.03 (m, 2H), 4.74 (ddd, J = 1676  found,10.1, 5.8, 2.2 Hz, 1H), cm−1 539.2604 4.06 (dd, J = 11.8, 6.8 Hz, 1H),3.91 (s, 3H), 3.80 (dd, J = 11.9, 4.9 Hz, 1H), 3.78-3.70 (m, 2H), 2.55(hept, J = 7.0 Hz, 1H), 2.16-2.08 (m, 1H), 2.07 (s, 3H), 1.55-1.44 (m,1H), 1.41 (d, J = 6.3 Hz, 3H), 1.39-1.29 (m, 1H) 1.29-1.19 (m, 4H), 1.17(dd, J = 7.0, 2.1 Hz, 6H), 0.87 (t, J = 6.9 Hz, 3H) 44 — (Thin HRMS-ESI¹H NMR (CDCl₃) δ 8.67 — Film) (m/z) (d, J = 7.8 Hz, 1H), 8.32 3378, [M +H]⁺ (d, J = 5.3 Hz, 1H), 7.34- 2954, calcd for 7.23 (m, 2H), 7.00-6.862873, C₂₈H₃₆N₂O₉, (m, 4H), 5.75 (d, J = 1.0 1748, 545.2494; Hz, 2H),5.24 (dq, J = 1676  found, 10.6, 6.3 Hz, 1H), 5.10 545.2503 (ddd, J =7.8, 5.4, 4.1 Hz, 1H), 4.10-4.01 (m, 4H), 3.92 (s, 3H), 3.73 (dd, J =11.4, 6.3 Hz, 1H), 2.13 (tt, J = 10.3, 3.8 Hz, 1H), 2.07 (s, 3H), 1.76(ddt, J = 13.8, 11.6, 4.1 Hz, 2H), 1.45 (d, J = 6.2 Hz, 3H), 1.42-1.10(m, 4H), 0.82 (t, J = 7.0 Hz, 3H) 45 — (Thin HRMS-ESI ¹H NMR (CDCl₃) δ11.99 — Film) (m/z) (d, J = 0.6 Hz, 1H), 8.81 3367, [M + H]⁺ (d, J = 8.0Hz, 1H), 8.04 2936, calcd for (d, J = 5.2 Hz, 1H), 7.34- 2873,C₂₅H₃₂N₂O₇, 7.25 (m, 2H), 6.95 (tt, J = 1745, 473.2282; 7.4, 1.0 Hz,1H), 6.92- 1649  found, 6.87 (m, 3H), 5.27 (dq, J = 473.2287 10.4, 6.3Hz, 1H), 5.08 (ddd, J = 8.0, 5.4, 3.9 Hz, 1H), 4.14-4.03 (m, 4H), 3.95(s, 3H), 3.72 (dd, J = 11.3, 6.1 Hz, 1H), 2.20- 2.08 (m, 1H), 1.76 (ddt,J = 13.7, 11.5, 4.2 Hz, 1H), 1.46 (d, J = 6.3 Hz, 3H), 1.43-1.11 (m,5H), 0.83 (t, J = 7.1 Hz, 3H) 46 104- — HRMS-ESI ¹H NMR (CDCl₃) δ 12.00— 106 (m/z) (s, 1H), 8.75 (d, J = 8.0 [M + H]⁺ Hz, 1H), 8.02 (d, J = 5.2calcd for Hz, 1H), 7.39-7.24 (m, C₂₇H₃₇N₂O₇, 5H), 6.87 (d, J = 5.2 Hz,501.2595; 1H), 5.14 (dq, J = 10.4, found, 6.3 Hz, 1H), 5.04 (ddd, J =501.2616 8.1, 6.2, 3.9 Hz, 1H), 4.65 (d, J = 11.2 Hz, 1H), 4.39 (d, J =11.2 Hz, 1H), 4.16-4.03 (m, 2H), 4.01- 3.92 (m, 4H), 3.72 (dd, J = 11.3,6.1 Hz, 1H), 3.33-3.24 (m, 1H), 2.00- 1.88 (m, 1H), 1.80- 1.66 (m, 1H),1.49-1.29 (m, 5H), 1.21-1.01 (m, 2H), 0.84 (app dd, J = 7.3, 6.6 Hz, 6H)47 66-70 — HRMS-ESI ¹H NMR (CDCl₃) δ 8.84 — (m/z) (d, J = 8.4 Hz, 1H),8.38 [M + H]⁺ (d, J = 5.4 Hz, 1H), 7.33- calcd for 7.24 (m, 2H), 7.02(d, J = C₂₈H₃₇N₂O₈, 5.5 Hz, 1H), 6.98-6.91 529.2544; (m, 1H), 6.91-6.85(m, found, 2H), 5.24 (dq, J = 10.4, 529.2558 6.2 Hz, 1H), 5.07 (ddd, J =8.0, 5.4, 4.1 Hz, 1H), 4.10-3.96 (m, 4H), 3.91 (s, 3H), 3.71 (dd, J =11.3, 6.3 Hz, 1H), 2.39 (s, 3H), 2.19-2.07 (m, 1H), 1.86- 1.71 (m, 1H),1.47- 1.32 (m, 5H), 1.29-1.15 (m, 1H), 1.10-0.97 (m, 1H), 0.81 (d, J =6.6 Hz, 3H), 0.77 (d, J = 6.6 Hz, 3H) 48 — (Thin HRMS-ESI ¹H NMR (CDCl₃)δ 8.60 — Film) (m/z) (d, J = 7.8 Hz, 1H), 8.29 3380, [M + H]⁺ (d, J =5.3 Hz, 1H), 6.96 2955, calcd for (d, J = 5.4 Hz, 1H), 5.79- 2875,C₂₆H₃₇F₃N₂O₉, 5.68 (m, 2H), 5.12 (dq, J = 1749, 579.2524; 10.4, 6.3 Hz,1H), 5.04 1676  found, (ddd, J = 7.8, 6.1, 3.8 Hz, 579.2528 1H), 4.03(dd, J = 12.1, 6.1 Hz, 1H), 3.98-3.92 (m, 2H), 3.91 (s, 3H), 3.66 (ddt,J = 14.5, 11.3, 5.9 Hz, 2H), 3.31 (dt, J = 9.3, 6.2 Hz, 1H), 3.09 (ddd,J = 10.0, 6.0, 1.1 Hz, 1H), 2.26-2.10 (m, 2H), 2.07 (s, 3H), 1.91- 1.74(m, 3H), 1.61 (ddt, J = 11.1, 8.3, 3.5 Hz, 1H), 1.39 (d, J = 6.2 Hz,3H), 1.37-1.13 (m, 5H), 0.90 (t, J = 6.9 Hz, 3H) 49 92-95 — ESIMS ¹H NMR(CDCl₃) δ 5.31 — m/z 450 (d, J = 8.2 Hz, 1H), 5.09- ([M + Na]⁺) 4.97 (m,1H), 4.75-4.60 (m, 2H), 3.99-3.89 (m, 1H), 3.78-3.63 (m, 3H), 2.13-2.01(m, 1H), 1.65- 1.54 (m, 1H), 1.53- 1.26 (m, 15H), 1.19-1.04 (m, 2H),1.05-0.93 (m, 2H), 0.90-0.82 (m, 8H) 50 — — ESIMS — — m/z 388 ([M + H]⁺)51 — — ESIMS ¹H NMR (CDCl₃) δ 7.31- ¹³C NMR (CDCl₃) m/z 458 7.22 (m,2H), 6.98- δ 170.91, 157.22, ([M + Na]⁺) 6.90 (m, 1H), 6.90-6.83 155.27,129.62, (m, 2H), 5.42 (d, J = 7.9 120.88, 115.09, Hz, 1H), 5.19 (dq, J =80.26, 80.09, 10.4, 6.2 Hz, 1H), 4.72- 78.29, 75.90, 4.63 (m, 1H),4.07-3.95 73.25, 54.71, (m, 2H), 3.90 (d, J = 4.9 50.29, 33.75, Hz, 2H),3.66 (dd, J = 28.50, 28.33, 11.3, 6.2 Hz, 1H), 2.16- 25.98, 22.48, 2.04(m, 1H), 1.82-1.69 22.32, 19.88 (m, 1H), 1.49-1.32 (m, 14H), 1.29-1.16(m, 1H), 1.10-0.97 (m, 1H), 0.81 (d, J = 6.6 Hz, 3H), 0.77 (d, J = 6.6Hz, 3H) 52 — — ESIMS ¹H NMR (CDCl₃) δ 8.85 — m/z 336 (bs, 3H), 7.35-7.27(m, ([M + H]⁺) 5H), 5.20-5.08 (m, 1H), 4.61 (d, J = 11.3 Hz, 1H), 4.55(dd, J = 5.8, 2.9 Hz, 1H), 4.45 (dd, J = 13.1, 2.9 Hz, 1H), 4.36 (d, J =11.4 Hz, 1H), 4.15 (d, J = 11.5 Hz, 1H), 4.05 (dd, J = 13.1, 5.8 Hz,1H), 3.61 (dd, J = 11.7, 5.8 Hz, 1H), 3.25 (dd, J = 9.9, 5.5 Hz, 1H),1.92-1.82 (m, 1H), 1.64 (t, J = 12.8 Hz, 1H), 1.37 (d, J = 6.3 Hz, 3H),1.34-1.15 (m, 4H), 1.15- 1.04 (m, 1H), 0.83 (t, J = 6.9 Hz, 3H) 53 54-57— HRMS-ESI ¹H NMR (CDCl₃) δ 11.99 — (m/z) (s, 1H), 8.73 (d, J = 8.1 [M +H]⁺ Hz, 1H), 7.99 (d, J = 5.2 calcd for Hz, 1H), 6.87 (d, J = 5.3C₂₃H₃₇N₂O₇, Hz, 1H), 5.19-5.07 (m, 453.2595; 1H), 5.07-4.97 (m, 1H),found, 4.09-3.91 (m, 6H), 3.68- 453.2608 3.52 (m, 2H), 3.29- 3.19 (m,1H), 3.08 (dd, J = 9.8, 6.0 Hz, 1H), 1.91- 1.80 (m, 1H), 1.77-1.64 (m,1H), 1.63-1.30 (m, 7H), 1.28-1.10 (m, 2H), 0.97-0.86 (m, 9H) 54 — —ESIMS ¹H NMR (CDCl₃) δ 7.19 ¹⁹F NMR (CDCl₃) m/z 452 (dd, J = 8.4, 5.6Hz, 2H), δ −117.31 ([M + H]⁺) 6.97 (t, J = 8.7 Hz, 2H), 5.35-5.29 (m,1H), 5.08 (dt, J = 12.4, 6.2 Hz, 1H), 4.65-4.56 (m, 1H), 4.00- 3.89 (m,2H), 3.85- 3.76 (m, 1H), 3.64 (dd, J = 11.5, 5.8 Hz, 1H), 3.34 (dd, J =10.1, 7.1 Hz, 1H), 3.21 (dd, J = 10.1, 6.6 Hz, 1H), 3.04 (dd, J = 9.4,5.9 Hz, 1H), 2.93 (dd, J = 14.7, 4.2 Hz, 1H), 2.70 (dd, J = 14.6, 6.0Hz, 1H), 2.13 (tt, J = 9.7, 5.3 Hz, 1H), 1.43 (s, 9H), 1.30 (d, J = 6.3Hz, 3H), 1.09- 0.95 (m, 1H), 0.58-0.46 (m, 2H), 0.25-0.11 (m, 2H) 55 — —ESIMS ¹H NMR (CDCl₃) 8 5.37 ¹³C NMR (CDCl₃) m/z 422 (d, J = 7.9 Hz, 1H),5.05 δ 171.17, 155.20, ([M + Na]⁺) (dq, J = 10.3, 6.3 Hz, 1H), 80.60,79.96, 4.62 (ddd, J = 8.0, 6.2, 3.9 79.73, 75.21, Hz, 1H), 3.98-3.86 (m,74.35, 73.59, 2H), 3.82-3.75 (m, 1H), 54.32, 50.00, 3.58 (dd, J = 11.2,6.3 Hz, 28.27, 27.97, 1H), 3.41 (dd, J = 10.0, 26.96, 23.39, 6.9 Hz,1H), 3.14 (dd, J = 19.89, 13.97, 10.0, 6.8 Hz, 1H), 3.05 10.68, 2.97(dd, J = 9.9, 6.2 Hz, 1H), 1.84 (tt, J = 10.1, 3.8 Hz, 1H), 1.70 (m,1H), 1.44 (s, 9H), 1.37 (d, J = 6.3 Hz, 3H), 1.33-1.16 (m, 5H), 1.01 (m,1H), 0.89 (t, J = 7.0 Hz, 3H), 0.58- 0.45 (m, 2H), 0.24-0.12 (m, 2H) 56— — ESIMS ¹H NMR (CDCl₃) δ 7.12- ¹⁹F NMR (CDCl₃) m /z 510 7.04 (m, 4H),6.91 (t, J = δ −116.99 ([M + Na]⁺) 8.7 Hz, 2H), 6.71 (d, J = 8.5 Hz,2H), 5.37 (d, J = 7.9 Hz, 1H), 5.17 (dq, J = 10.0, 6.3 Hz, 1H), 4.70-4.62 (m, 1H), 4.01 (d, J = 11.3 Hz, 1H), 3.97-3.80 (m, 3H), 3.68 (dd, J= 11.4, 6.1 Hz, 1H), 2.93 (dd, J = 14.7, 5.0 Hz, 1H), 2.83 (dd, J =14.7, 4.4 Hz, 1H), 2.37 (tt, J = 9.8, 4.7 Hz, 1H), 2.29 (s, 3H), 1.46(d, J = 6.3 Hz, 3H), 1.44 (s, 9H) 57 45-50 — HRMS-ESI ¹H NMR (CDCl₃) δ8.55 — (m/z) (d, J = 8.1 Hz, 1H), 8.29 [M + H]⁺ (d, J = 5.3 Hz, 1H),6.96 calcd for (d, J = 5.4 Hz, 1H), 5.77- C₂₇H₃₉N₂O₁₀, 5.69 (m, 2H),5.13-5.03 551.2599; (m, 2H), 4.80-4.71 (m, found, 1H), 4.07 (dd, J =11.8, 551.2610 6.8 Hz, 1H), 3.91 (s, 3H), 3.84-3.74 (m, 3H), 2.07 (s,4H), 1.67-1.28 (m, 7H), 1.19-1.06 (m, 2H), 1.04-0.96 (m, 2H), 0.91- 0.82(m, 8H) 58 — (Thin ESIMS ¹H NMR (CDCl₃) δ 11.95 — Film) m/z 467 (d, J =0.6 Hz, 1H), 8.70 3376, ([M + H]⁺) (d, J = 8.3 Hz, 1H), 8.00 2963, (d, J= 5.2 Hz, 1H), 6.88 2873, (d, J = 5.2 Hz, 1H), 5.16- 1728, 5.02 (m, 2H),4.74 (ddd, J = 1641  10.1, 4.7, 3.1 Hz, 1H), 4.09-4.03 (m, 1H), 3.94 (s,3H), 3.84 (dd, J = 11.9, 4.8 Hz, 1H), 3.79-3.75 (m, 2H), 2.56 (p, J =7.0 1H), 1.58-1.45 (m, 1H), 1.42 (d, J = 6.3 Hz, 3H), 1.40-1.29(m, 1H),1.30- 1.19 (m, 4H), 1.18 (dd, J = 7.0, 2.1 Hz, 6H), 0.88 (t, J = 6.9 Hz,3H) 59 — — HRMS-ESI ¹H NMR (CDCl₃) δ 8.57 ¹⁹F NMR (CDCl₃) (m/z) (d, J =7.9 Hz, 1H), 8.29 δ −116.84 [M + H]⁺ (d, J = 5.3 Hz, 1H), 7.17 calcd for(dd, J = 8.5, 5.5 Hz, 2H), C₂₉H₃₄FN₂O₁₀, 7.02-6.93 (m, 3H), 5.83-589.2192; 5.65 (m, 2H), 5.19- found, 5.03 (m, 2H), 4.77 (ddd, J =589.2189 9.3, 5.1, 2.2 Hz, 1H), 4.14 (dd, J = 11.6, 6.5 Hz, 1H), 3.91(s, 3H), 3.88- 3.75 (m, 3H), 2.79 (dd, J = 14.8, 6.3 Hz, 1H), 2.67 (dd,J = 14.8, 5.5 Hz, 1H), 2.55-2.42 (m, 1H), 2.06 (s, 3H), 1.50 (tt, J =8.0, 4.6 Hz, 1H), 1.39 (d, J = 6.4 Hz, 3H), 1.00-0.92 (m, 2H), 0.92-0.78(m, 2H) 60 58-62 — HRMS-ESI ¹H NMR (CDCl₃) δ 11.98 — (m/z) (s, 1H), 8.80(d, J = 8.0 [M + H]⁺ Hz, 1H), 8.04 (d, J = 5.2 calcd for Hz, 1H),7.33-7.23 (m, C₂₆H₃₅N₂O₇, 2H), 6.99-6.85 (m, 4H), 487.2439; 5.27 (dq, J= 10.4, 6.3 Hz, found, 1H), 5.07 (ddd, J = 8.0, 487.2469 5.4, 3.8 Hz,1H), 4.15- 3.99 (m, 4H), 3.95 (s, 3H), 3.72 (dd, J = 11.4, 6.2 Hz, 1H),2.21-2.09 (m, 1H), 1.86-1.72 (m, 1H), 1.49-1.34 (m, 5H), 1.31-1.17 (m,1H), 1.12- 0.99 (m, 1H), 0.82 (d, J = 6.6 Hz, 3H), 0.78 (d, J = 6.6 Hz,3H) 61 — — ESIMS ¹H NMR (CDCl₃) δ 7.32- — m/z 322 7.23 (m, 2H), 6.94(td, J = [M + H]⁺ 7.4, 1.1 Hz, 1H), 6.91- 6.86 (m, 2H), 5.08 (dq, J =10.5, 6.3 Hz, 1H), 4.02 (ddd, J = 9.9, 6.5, 1.1 Hz, 1H), 3.97-3.86 (m,2H), 3.83 (dd, J = 6.7, 4.6 Hz, 1H), 3.72 (dd, J = 10.9, 6.6 Hz, 1H),3.63 (dd, J = 11.5, 4.6 Hz, 1H), 2.09 (tt, J = 10.2, 3.9 Hz, 1H),1.77-1.66 (m, 2H), 1.42 (d, J = 6.3 Hz, 3H), 1.34- 1.01 (m, 4H),0.93-0.77 (m, 5H) 62 — — HRMS-ESI ¹H NMR (CDCl₃) δ 8.59 ¹⁹F NMR (CDCl₃)(m/z) (d, J = 7.8 Hz, 1H), 8.28 δ −117.38 [M + H]⁺ (d, J = 5.3 Hz, 1H),7.22- calcd for 7.13 (m, 2H), 7.02-6.90 C₂₈H₃₆FN₂O₉, (m, 3H), 5.77-5.67(m, 563.2399; 2H), 5.12 (dq, J = 9.6, 6.3 found, Hz, 1H), 5.04 (ddd, J =563.2414 7.8, 6.1, 3.7 Hz, 1H), 4.07 (dd, J = 12.1, 6.1 Hz, 1H), 4.01(d, J = 11.2 Hz, 1H), 3.92 (dd, J = 12.1, 3.8 Hz, 1H), 3.91 (s, 3H),3.71 (dd, J = 11.5, 5.8 Hz, 1H), 3.55 (dt, J = 9.0, 6.6 Hz, 1H), 3.25(dt, J = 8.9, 6.6 Hz, 1H), 3.08 (dd, J = 9.6, 5.8 Hz, 1H), 2.92 (dd, J =14.7, 4.1 Hz, 1H), 2.71 (dd, J = 14.7, 6.0 Hz, 1H), 2.22-2.09 (m, 1H),2.06 (s, 3H), 1.64-1.51 (m, 2H), 1.32 (d, J = 6.3 Hz, 3H), 0.91 (t, J =7.4 Hz, 3H) 63 — — ESIMS — — m/z 336 ([M + H]⁺) 64 — — HRMS-ESI ¹H NMR(CDCl₃) δ 8.62 ¹⁹F NMR (CDCl₃) (m/z) (d, J = 7.7 Hz, 1H), 8.30 δ −116.97[M + H]⁺ (d, J = 5.4 Hz, 1H), 7.14- calcd for 7.04 (m, 4H), 6.96 (d, J =C₃₂H₃₆FN₂O₉, 5.4 Hz, 1H), 6.91 (t, J = 611.2399; 8.7 Hz, 2H), 6.74 (d, J= found, 8.6 Hz, 2H), 5.79-5.64 611.2400 (m, 2H), 5.21 (dq, J = 10.0,6.2 Hz, 1H), 5.09 (ddd, J = 7.8, 5.9, 3.6 Hz, 1H), 4.08-3.93 (m, 4H),3.91 (s, 3H), 3.75 (dd, J = 11.3, 6.2 Hz, 1H), 2.96 (dd, J = 14.7, 4.9Hz, 1H), 2.84 (dd, J = 14.7, 4.3 Hz, 1H), 2.41 (tt, J = 9.8, 4.6 Hz,1H), 2.28 (s, 3H), 2.06 (s, 3H), 1.49 (d, J = 6.3 Hz, 3H) 65 — (ThinHRMS-ESI ¹H NMR (CDCl₃) δ 11.98 — Film) (m/z) (s, 1H), 8.74 (d, J = 8.13359, [M + H]⁺ Hz, 1H), 8.01 (d, J = 5.2 2956, calcd for Hz, 1H), 6.88(d, J = 5.2 2873, C₂₃H₃₃F₃N₂O₇, Hz, 1H), 5.14 (dq, J = 1746, 507.2313;10.3, 6.3 Hz, 1H), 5.02 1644  found, (ddd, J = 8.0, 6.0, 3.7 Hz,507.2320 1H), 4.04 (dd, J = 12.1, 6.0 Hz, 1H), 3.97 (d, J = 3.8 Hz, 1H),3.96-3.93 (m, 4H), 3.67 (ddt, J = 13.8, 11.4, 5.6 Hz, 2H), 3.32 (dt, J =9.2, 6.2 Hz, 1H), 3.10 (ddd, J = 10.0, 5.8, 1.1 Hz, 1H), 2.26- 2.10 (m,2H), 1.93-1.76 (m, 3H), 1.63 (ddt, J = 15.0, 11.1, 4.3 Hz, 1H), 1.40 (d,J = 6.3 Hz, 3H), 1.38-1.23 (m, 5H), 0.91 (t, J = 7.0 Hz, 3H) 66 112- —ESIMS ¹H NMR (CDCl₃) δ 5.41 — 115 m/z 382 (d, J = 8.2 Hz, 1H), 4.95([M + Na]⁺) (dq, J = 9.7, 6.3 Hz, 1H), 4.74-4.46 (m, 1H), 4.00 (dd, J =11.8, 6.8 Hz, 1H), 3.80-3.70 (m, 2H), 3.62- 3.50 (m, 2H), 2.28- 2.14 (m,1H), 1.88-1.76 (m, 1H), 1.69-1.57 (m, 1H), 1.53-1.37 (m, 14H), 1.30-1.07(m, 2H), 0.88 (app d, J = 6.6 Hz, 6H) 67 55-61 — HRMS-ESI ¹H NMR (CDCl₃)δ 8.78 — (m/z) (d, J = 8.2 Hz, 1H), 8.35 [M + H]⁺ (d, J = 5.4 Hz, 1H),7.38- calcd for 7.24 (m, 5H), 7.01 (d, J = C₂₉H₃₉N₂O₈, 5.4 Hz, 1H),5.17-5.00 543.2701; (m, 2H), 4.65 (d, J = 11.2 found, Hz, 1H), 4.38 (d,J = 11.2 543.2702 Hz, 1H), 4.14-3.99 (m, 2H), 3.94-3.85 (m, 4H), 3.71(dd, J = 11.2, 6.3 Hz, 1H), 3.33-3.23 (m, 1H), 2.39 (s, 3H), 1.98-1.85(m, 1H), 1.80-1.66 (m, 1H), 1.47-1.28 (m, 5H), 1.20-1.00 (m, 2H), 0.88-0.80 (m, 6H) 68 70-75 — HRMS-ESI ¹H NMR (CDCl₃) δ 8.72 — (m/z) (d, J =8.4 Hz, 1H), 8.34 [M + H]⁺ (d, J = 5.3 Hz, 1H), 7.01 calcd for (d, J =5.5 Hz, 1H), 5.13- C2₆H₃₇N₂O₉, 5.00 (m, 2H), 4.75 (ddd, J = 521.2494;10.1, 5.2, 2.7 Hz, 1H), found, 4.04 (dd, J = 11.8, 6.8 Hz, 521.2495 1H),3.90 (s, 3H), 3.81- 3.72 (m, 3H), 2.38 (s, 3H), 2.16-2.04 (m, 1H),1.66-1.28 (m, 7H), 1.18- 1.06 (m, 2H), 1.04- 0.95 (m, 2H), 0.91-0.82 (m,8H) 69 — — ESIMS — — m/z 350 ([M + H]⁺) 70 — — ESIMS ¹H NMR (CDCl₃) δ7.39- ¹³C NMR (CDCl₃) m/z 522 7.14 (m, 10H), 5.33 (d, δ 171.40, 155.17,([M + Na]⁺) J = 8.1 Hz, 1H), 5.15- 140.35, 137.58, 5.03 (m, 1H), 4.83(d, J = 129.00, 128.47, 7.0 Hz, 1H), 4.70 (d, J = 128.45, 127.77, 7.0Hz, 1H), 4.66-4.63 127.76, 126.14, (m, 1H), 4.60 (d, J = 4.3 94.13,80.50, Hz, 2H), 4.05 (dd, J = 80.05, 77.06, 11.7, 6.3 Hz, 1H), 3.92-74.11, 74.10, 3.86 (m, 1H), 3.80 (dd, J = 70.20, 53.95, 11.6, 5.4 Hz,1H), 3.68 51.15, 36.11, (dd, J = 11.7, 4.6 Hz, 1H), 28.32, 21.10 3.55(ddd, J = 8.9, 5.4, 2.0 Hz, 1H), 2.98 (dd, J = 14.7, 4.5 Hz, 1H), 2.64(dd, J = 14.7, 7.2 Hz, 1H), 2.40-2.26 (m, 1H), 1.44 (s, 9H), 1.28 (d, J= 6.4 Hz, 3H) 71 — (Thin HRMS-ESI ¹H NMR (CDCl₃) δ 8.57 — Film) (m/z)(d, J = 7.8 Hz, 1H), 8.28 3377, [M + H]⁺ (d, J = 5.3 Hz, 1H), 7.27-2934, calcd for 7.12 (m, 2H), 7.02-6.90 1748, C₂₉H₃₆FN₂O₉, (m, 3H),5.77-5.67 (m, 1676, 575.2399; 2H), 5.13 (dq, J = 9.6, 6.3 1508  found,Hz, 1H), 5.04 (ddd, J = 575.2453 7.8, 6.1, 3.7 Hz, 1H), 4.05 (dd, J =12.1, 6.1 Hz, 1H), 4.00 (d, J = 11.0 Hz, 1H), 3.95-3.90 (m, 1H), 3.90(s, 3H), 3.71 (dd, J = 11.5, 5.9 Hz, 1H), 3.36 (dd, J = 10.1, 7.0 Hz,1H), 3.23 (dd, J = 10.2, 6.5 Hz, 1H), 3.11 (ddd, J = 9.7, 5.9, 1.4 Hz,1H), 2.95 (dd, J = 14.7, 4.2 Hz, 1H), 2.72 (dd, J = 14.7, 6.0 Hz, 1H),2.22-2.11 (m, 1H), 2.05 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H), 1.09-0.95 (m,1H), 0.58-0.47 (m, 2H), 0.27-0.12 (m, 2H) 72 — (Thin HRMS-ESI ¹H NMR(CDCl₃) δ 11.98 — Film) (m/z) (d, J = 0.7 Hz, 1H), 8.71 3369, [M + H]⁺(d, J = 8.1 Hz, 1H), 8.00 3028, calcd for (d, J = 5.2 Hz, 1H), 7.38-2938, C₃₀H₃₅N₂O₈, 7.21 (m, 9H), 7.23-7.17 1744, 551.2388; (m, 1H), 6.86(d, J = 5.2 1649, found, Hz, 1H), 5.17 (dq, J = 8.3, 1577, 551.2388 6.4Hz, 1H), 5.04 (ddd, J = 1528, 8.1, 6.4, 4.6 Hz, 1H), 1453  4.85 (d, J =7.0 Hz, 1H), 4.73 (d, J = 7.0 Hz, 1H), 4.65 (d, J = 11.9 Hz, 1H), 4.60(d, J = 11.8 Hz, 1H), 4.19 (dd, J = 11.7, 6.4 Hz, 1H), 3.98-3.94 (m,1H), 3.93 (s, 3H), 3.87 (dd, J = 11.8, 5.5 Hz, 1H), 3.83 (dd, J = 11.7,4.7 Hz, 1H), 3.62 (ddd, J = 8.8, 5.4, 2.0 Hz, 1H), 3.00 (dd, J = 14.7,4.5 Hz, 1H), 2.69 (dd, J = 14.7, 7.2 Hz, 1H), 2.36 (tdd, J = 8.5, 7.2,4.5 Hz, 1H), 1.31 (d, J = 6.4 Hz, 3H) 73 — — HRMS-ESI ¹H NMR (CDCl₃) δ8.78 ¹³C NMR (CDCl₃) (m/z) (d, J = 7.5 Hz, 1H), 8.36 δ 170.11, 169.38,[M + H]⁺ (d, J = 5.4 Hz, 1H), 7.34- 162.77, 159.45, calcd for 7.09 (m,7H), 7.01 (d, J = 156.58, 146.88, C₃₂H₃₆N₂O₉, 5.5 Hz, 1H), 6.96 (t, J =141.24, 139.10, 592.2421; 7.3 Hz, 1H), 6.85 (d, J = 129.68, 129.40,found, 7.9 Hz, 2H), 5.31-5.18 128.38, 126.23, 592.2426 (m, 1H),5.12-4.95 (m, 121.00, 115.28, 1H), 4.10-3.91 (m, 4H), 109.93, 78.95,3.89 (s, 3H), 3.80 (t, J = 78.18, 77.25, 6.6 Hz, 2H), 3.40 (s, 3H),74.99, 73.21, 2.97 (t, J = 6.6 Hz, 2H), 67.57, 58.79, 2.92 (t, J = 4.8Hz, 2H), 56.34, 53.08, 2.46 (tt, J = 9.7, 4.7 Hz, 51.57, 35.06, 1H),1.47 (d, J = 6.3 Hz, 34.60, 20.64 3H) 74 — — ESIMS ¹H NMR (CDCl₃) δ7.32- ¹³C NMR (CDCl₃) m/z 433.3 7.14 (m, 5H), 5.35 (d, J = δ 170.95,155.21, [M + H]⁺ 7.7 Hz, 1H), 5.15-5.05 140.24, 129.24, (m, 1H),4.65-4.56 (m, 128.34, 126.03, 1H), 4.00-3.88 (m, 2H), 81.45, 79.99,3.84-3.78 (m, 1H), 3.66 79.27, 75.26, (dd, J = 11.5, 5.8 Hz, 1H), 73.97,54.42, 3.34 (dd, J = 10.1, 7.1 Hz, 51.80, 35.53, 1H), 3.22 (dd, J =10.0, 31.59, 28.29, 6.6 Hz, 1H), 3.11-2.94 20.77, 10.70, 3.17 (m, 2H),2.72 (dd, J = 14.6, 6.2 Hz, 1H), 2.23- 2.15 (m, 1H), 1.43 (s, 9H), 1.29(d, J = 6.3 Hz, 3H), 1.08-0.99 (m, 1H), 0.57-0.46 (m, 2H), 0.24- 0.12(m, 2H) 75 — — ESIMS — — m/z 355.3 ([M − Cl]⁺) 76 — — HRMS-ESI ¹H NMR(CDCl₃) δ 11.99 ¹³C NMR (CDCl₃) (m/z) (s, 1H), 8.73 (d, J = 8.0 δ169.90, 168.96, [M + H]⁺ Hz, 1H), 8.01 (d, J = 5.2 155.32, 148.73, calcdfor Hz, 1H), 7.44-7.08 (m, 140.63, 140.30, C₂₆H₃₄N₂O₇, 5H), 6.87 (d, J =5.2 Hz, 130.32, 129.18, 486.2366; 1H), 5.16 (dq, J = 9.5, 6.3 128.37,126.04, found, Hz, 1H), 5.04-4.97 (m, 109.53, 81.79, 486.2374 1H),4.17-3.95 (m, 3H), 79.11, 76.13, 3.94 (s, 3H), 3.72 (dd, J = 74.59,74.38, 11.6, 5.6 Hz, 1H), 3.37 56.08, 53.04, (dd, J = 8.8, 6.5 Hz, 1H),51.86, 35.45, 3.16-3.07 (m, 2H), 3.03 28.85, 20.82, 19.54 (dd, J = 14.6,3.9 Hz, 1H), 2.71 (dd, J = 14.6, 6.5 Hz, 1H), 2.25-2.15 (m, 1H), 1.84(dp, J = 13.2, 6.6 Hz, 1H), 1.29 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 6.8Hz, 6H) 77 49-54 — HRMS-ESI ¹H NMR (CDCl₃) δ 11.97 — (m/z) (s, 1H), 8.77(d, J = 8.0 [M + H]⁺ Hz, 1H), 8.03 (d, J = 5.2 calcd for Hz, 1H),7.38-7.09 (m, C₂₈H₃₀N₂O₇, 7H), 6.96 (t, J = 7.4 Hz, 506.2053; 1H), 6.87(dd, J = 11.2, found, 6.5 Hz, 3H), 5.35-5.20 506.2062 (m, 1H), 5.07 (dt,J = 9.0, 4.6 Hz, 1H), 4.14-4.01 (m, 4H), 3.95 (s, 3H), 3.78 (dd, J =11.4, 6.1 Hz, 1H), 3.03-2.85 (m, 2H), 2.48 (tt, J = 9.8, 4.8 Hz, 1H),1.49 (d, J = 6.3 Hz, 3H) 78 — — ESIMS — — m/z 335.2 ([M − Cl]⁺) 79 52-57— HRMS-ESI ¹H NMR (CDCl₃) δ 8.76 — (m/z) (d, J = 7.3 Hz, 1H), 8.34 [M +H]⁺ (d, J = 5.4 Hz, 1H), 7.33- calcd for 7.13 (m, 5H), 7.00 (d, J =C₂₈H₃₆N₂O₈, 5.5 Hz, 1H), 5.20-5.06 528.2472; (m, 1H), 5.06-4.89 (m,found, 1H), 4.08-3.86 (m, 3H), 528.2475 3.89 (s, 3H), 3.70 (dd, J =11.4, 5.8 Hz, 1H), 3.37 (dd, J = 8.8, 6.5 Hz, 1H), 3.14-3.06 (m, 2H),3.02 (dd, J = 14.6, 3.8 Hz, 1H), 2.69 (dd, J = 14.6, 6.4 Hz, 1H), 2.38(s, 3H), 2.28- 2.11 (m, 1H), 1.84 (dq, J = 13.3, 6.7 Hz, 1H), 1.27 (d, J= 6.4 Hz, 3H), 0.90 (t, J = 6.8 Hz, 6H) 80 — — HRMS-ESI ¹H NMR (CDCl₃) δ8.59 ¹³C NMR (CDCl₃) (m/z) (d, J = 7.4 Hz, 1H), 8.28 δ 170.51, 170.25,[M + H]⁺ (d, J = 5.5 Hz, 1H), 7.37- 163.26, 160.22, calcd for 7.14 (m,5H), 6.95 (d, 145.81, 143.96, C₂₉H₃₆N₂O₉, 5.0 Hz, 1H), 5.77-5.67 142.23,140.26, 556.2421; (m, 2H), 5.20-5.07 (m, 129.26, 128.35, found, 1H),5.06-5.02 (m, 1H), 126.03, 109.67, 556.2424 4.10-3.92 (m, 3H), 3.9089.47, 81.42, (s, 3H), 3.72 (dd, J = 11.4, 79.10, 77.25, 6.0 Hz, 1H),3.35 (dd, J = 74.78, 73.99, 10.1, 7.1 Hz, 1H), 3.24 56.19, 53.22, (dd, J= 10.1, 6.6 Hz, 1H), 51.77, 35.53, 3.12 (dd, J = 9.7, 5.0 Hz, 20.87,10.72, 3.18, 1H), 3.01 (dd, J = 14.6, 3.05 4.1 Hz, 1H), 2.75 (dd, J =14.6, 6.2 Hz, 1H), 2.26- 2.17 (m, 1H), 2.06 (s, 3H), 1.32 (d, J = 6.3Hz, 3H), 1.10-0.96 (m, 1H), 0.57-0.46 (m, 2H), 0.23- 0.13 (m, 2H) 8175-81 — HRMS-ESI ¹H NMR (CDCl₃) δ 8.80 — (m/z) (d, J = 7.5 Hz, 1H), 8.36[M + H]⁺ (d, J = 5.4 Hz, 1H), 7.33- calcd for 7.09 (m, 7H), 7.00 (d, J =C₃₀H₃₂N₂O₈, 5.5 Hz, 1H), 6.95 (t, J = 548.2159; 7.4 Hz, 1H), 6.85 (d, J= found, 8.7 Hz, 2H), 5.30-5.16 548.2159 (m, 1H), 5.10-5.03 (m, 1H),4.10-3.92 (m, 4H), 3.89 (s, 3H), 3.76 (dd, J = 11.4, 6.3 Hz, 1H), 3.01-2.79 (m, 2H), 2.46 (tt, J = 9.8, 4.7 Hz, 1H), 2.38 (s, 3H), 1.47 (d, J =6.3 Hz, 3H) 82 — — ESIMS ¹H NMR (CDCl₃) δ 7.35- ¹³C NMR (CDCl₃) m/z435.4 7.00 (m, 5H), 5.39 (d, J = δ 170.93, 155.22, [M + H]⁺ 7.7 Hz, 1H),5.09 (dq, J = 140.35, 129.17, 12.6, 6.3 Hz, 1H), 4.60 128.33, 126.00,(t, J = 8.4 Hz, 1H), 4.04- 81.84, 79.95, 3.90 (m, 2H), 3.82 (dd, J =79.08, 76.07, 12.0, 3.3 Hz, 1H), 3.65 75.30, 74.04, (dd, J = 11.5, 5.6Hz, 1H), 54.49, 51.86, 3.36 (dd, J = 8.8, 6.5 Hz, 35.43, 28.84, 1H),3.13-2.92 (m, 3H), 28.30, 20.78, 19.58 2.67 (dd, J = 14.6, 6.4 Hz, 1H),2.27-2.09 (m, 1H), 1.82 (hept, J = 6.6 Hz, 1H), 1.43 (s, 9H), 1.25 (d, J= 6.4 Hz, 3H), 0.89 (t, J = 6.8 Hz, 6H) 83 — — HRMS-ESI ¹H NMR (CDCl₃) δ11.98 ¹³C NMR (CDCl₃) (m/z) (s, 1H), 8.72 (d, J = 8.0 δ 169.89, 168.95,[M + H]⁺ Hz, 1H), 7.99 (d, J = 5.2 155.31, 148.72, calcd for Hz, 1H),7.37-7.11 (m, 140.63, 140.17, C₂₆H₃₂N₂O₇, 5H), 6.86 (d, J = 5.2 Hz,130.28, 129.25, 484.221; 1H), 5.29-5.10 (m, 1H), 128.37, 126.07, found,5.05-4.97 (m, 1H), 4.15- 109.54, 81.38, 484.221 3.95 (m, 3H), 3.93 (s,79.37, 74.55, 3H), 3.72 (dd, J = 11.5, 74.25, 74.00, 5.8 Hz, 1H), 3.36(dd, J = 56.08, 52.99, 10.1, 7.1 Hz, 1H), 3.25 51.79, 35.54, (dd, J =10.1, 6.6 Hz, 1H), 20.80, 10.72, 3.19 3.13 (dd, J = 9.2, 5.2 Hz, 1H),3.01 (dd, J = 14.5, 4.1 Hz, 1H), 2.76 (dd, J = 14.5, 6.2 Hz, 1H), 2.31-2.16 (m, 1H), 1.33 (d, J = 6.3 Hz, 3H), 1.11-0.94 (m, 1H), 0.59-0.45 (m,2H), 0.27-0.10 (m, 2H) 84 — — HRMS-ESI ¹H NMR (CDCl₃) δ 8.63 ¹³C NMR(CDCl₃) (m/z) (d, J = 7.6 Hz, 1H), 8.31 δ 170.25, 163.32, [M + H]⁺ (d, J= 5.2 Hz, 1H), 7.36- 160.23, 156.58, calcd for 7.08 (m, 7H), 6.96 (d, J= 145.87, 139.10, C₃₁H₃₄N₂O₉, 7.2 Hz, 2H), 6.85 (d, J = 129.67, 129.40,578.2264; 8.6 Hz, 2H), 5.73 (d, J = 128.38, 126.23, found, 2.7 Hz, 2H),5.30-5.17 120.99, 115.28, 578.2263 (m, 1H), 5.15-5.03 (m, 109.74, 89.43,1H), 4.09-3.98 (m, 4H), 86.87, 79.14, 3.91 (s, 3H), 3.78 (dd, J = 78.21,77.27, 11.5, 6.3 Hz, 1H), 3.00- 75.10, 73.20, 2.83 (m, 2H), 2.47 (tt, J= 57.02, 56.22, 9.7, 4.7 Hz, 1H), 2.06 (s, 53.39, 51.59, 3H), 1.48 (d, J= 6.3 Hz, 35.07, 20.86, 20.64 3H) 85 — — HRMS-ESI ¹H NMR (CDCl₃) δ 8.60¹³C NMR (CDCl₃) (m/z) (d, J = 7.7 Hz, 1H), 8.29 δ 170.52, 170.24, [M +H]⁺ (d, J = 5.4 Hz, 1H), 7.33- 163.27, 160.22, calcd for 7.13 (m, 5H),6.95 (d, J = 145.81, 143.95, C₂₉H₃₈N₂O₉, 5.4 Hz, 1H), 5.73 (d, J =142.24, 140.39, 558.2577; 1.7 Hz, 2H), 5.17-5.11 129.18, 128.34, found,(m, 1H), 5.07-4.90 (m, 125.99, 109.68, 558.2588 1H), 4.16-3.91 (m, 3H),89.46, 81.79, 3.91 (s, 3H), 3.72 (dd, J = 78.82, 76.08, 11.5, 5.8 Hz,1H), 3.37 74.79, 74.15, (dd, J = 8.8, 6.5 Hz, 1H), 60.38, 56.19,3.12-3.07 (m, 2H), 3.06- 53.26, 51.83, 2.98 (m, 1H), 2.70 (dd, 35.43,28.85, J = 14.6, 6.4 Hz, 1H), 20.87, 19.53 2.28-2.18 (m, 1H), 2.06 (s,3H), 1.88-1.78 (m, 1H), 1.29 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 6.8 Hz,6H) 86 — — ESIMS m/z 333.2 — — ([M − Cl]⁺) 87 54-59 — HRMS-ESI ¹H NMR(CDCl₃) δ 8.75 — (m/z) [M + H]⁺ (d, J = 7.4 Hz, 1H), 8.33 calcd for (d,J = 5.4 Hz, 1H), 7.32- C₂₈H₃₄N₂O₈, 7.14 (m, 5H), 6.99 (d, J = 526.2315;5.5 Hz, 1H), 5.19-5.07 found, (m, 1H), 5.04-4.97 (m, 526.2320 1H),4.08-3.95 (m, 2H), 3.89 (s, 3H), 3.89-3.83 (m, 1H), 3.71 (dd, J = 11.3,6.0 Hz, 1H), 3.35 (dd, J = 10.1, 7.1 Hz, 1H), 3.24 (dd, J = 10.1, 6.6Hz, 1H), 3.12 (dd, J = 10.1, 5.4 Hz, 1H), 3.00 (dd, J = 14.6, 4.0 Hz,1H), 2.75 (dd, J = 14.6, 6.2 Hz, 1H), 2.38 (s, 3H), 2.27-2.15 (m, 1H),1.31 (d, J = 6.3 Hz, 3H), 1.11-0.97 (m, 1H), 0.56-0.48 (m, 2H),0.26-0.13 (m, 2H) *¹H NMR were run at 400 MHz unless noted otherwise*¹³C NMR were run at 101 MHz unless noted otherwise *¹⁹F NMR were run at376 MHz unless noted otherwise

TABLE 3 Biological Testing Rating Scale Rating Table for FungalPathogens % Control Rating >70 A ≦70 B Not Tested C

TABLE 4 Biological Activity - PUCCRT and SEPTTR Disease Control in Highand Low Volume Applications PUCCRT* SEPTTR* 1DP* 3DC* 1DP* 3DC* Cmpd.Rate Rate No. 121.5 g/H* 100 ppm* 121.5 g/H* 100 ppm* 121.5 g/H* 100ppm* 121.5 g/H* 100 ppm* 3 C A C A C A C B 6 A C A C A C A C 8 A C A C AC A C 9 A C A C A C A C 10 A C B C A C A C 14 A C A C A C A C 17 C A C AC A C A 18 A C A C B C A C 20 A C A C A C A C 23 C A C B C A C B 24 C AC A C A C A 25 C A C A C A C A 26 C A C A C A C A 28 A C A C A C A C 30A C A C A C A C 32 A C A C A C A C 36 C B C B C B C A 37 C A C A C A C A38 C A C A C A C A 40 A C A C A C A C 43 A C A C B C A C 44 A C A C A CA C 45 C A C B C A C B 46 C A C A C A C B 47 A C B C A C A C 48 A C A CA C A C 53 C A C A C B C B 57 A C A C B C A C 58 C A C B C B C A 59 A CA C A C A C 60 C A C A C A C B 62 A C A C A C A C 64 A C B C A C A C 65C A C B C A C A 67 A C A C A C A C 68 A C A C B C A C 71 A C A C A C A C72 C A C B C B C B 73 A C A C A C A C 76 C C C C C C C C 77 C C C C C CC C 79 A C A C A C A C 80 A A A A A A A A 81 A C A C A C A C 83 C A C AC A C A 84 A C A C A C A C 85 A A A A A B A A 87 C A C A C A C A*PUCCRT—Wheat Brown Rust (Puccinia triticina) *SEPTTR—Wheat Leaf Blotch(Septoria tritici) *1DP—1 Day Protectant *3DC—3 Day Curative *g/H—GramsPer Hectare *ppm—Parts Per Million

TABLE 5 Biological Activity-Disease Control at 100 ppm Compound. ALTESO*CERCBE* COLLLA* ERYSCI* ERYSGH* Number 1 DP* 6 B A A A A 9 B B A B B*ALTESO—Tomato Early Blight (Alternaria solani) *CERCBE—Leaf Spot ofSugar Beets (Cercospora beticola) *COLLLA—Cucumber Anthracnose(Glomerella lagenarium; Anamorph: Colletotricum lagenarium)*ERYSCI—Powdery Mildew of Cucumber (Erysiphe cichoracearum)*ERYSGH—Barley Powdery Mildew (Blumeria graminis f. sp. hordei; Synonym:Erysiphe graminis f. sp. hordei) *1 DP—1 Day Protectant

TABLE 6 Biological Activity-Disease Control at 100 ppm Compound. LEPTNO*PYRIOR* RHYNSE* UNCINE* Number 1 DP* 6 A A A A 9 A B A A *LEPTNO—WheatGlume Blotch (Leptosphaeria nodorum) *RHYNSE—Rice Blast (Magnaporthegrisea; Anamorph: Pyricularia oryzae) *RHYNSE—Barley Scald(Rhyncosporium secalis) *UNCINE—Grape Powdery Mildew (Uncinula necator)*1 DP—1 Day Protectant

What is claimed is:
 1. A compound of Formula I

wherein X is hydrogen or C(O)R₃; Y is hydrogen, C(O)R₃, or Q; Q is

R₁ is hydrogen, alkyl, alkenyl, aryl, alkoxy, or acyl, each optionallysubstituted with 0, 1 or multiple R₆; R₂ is hydrogen, alkyl, aryl,—Si(R₅)₃, alkenyl, or acyl, each optionally substituted with 0, 1 ormultiple R₆; R₃ is alkoxy or benzyloxy, each optionally substituted with0, 1, or multiple R₆; R₄ is hydrogen, —C(O)R₅, or —CH₂OC(O)R₅; R₅ isalkyl, alkoxy, or aryl, each optionally substituted with 0, 1, ormultiple R₆; R₆ is hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy,hetcroaryl, hetcrocyclyl, or thioalkyl, each optionally substituted with0, 1, or multiple R₇; and R₇ is hydrogen, alkyl, aryl, or halo, whereinacyl refers to —C(═O)-cyclopropyl or —C(═O)—CH(CH₃)₂.
 2. A compoundaccording to claim 1, wherein X and Y are hydrogen.
 3. A compoundaccording to claim 2, wherein R₁ is chosen from alkyl and aryl, eachoptionally substituted with 0, 1 or multiple R₆.
 4. A compound accordingto claim 2, wherein R₂ is chosen from hydrogen, alkyl, aryl, and acyl,each optionally substituted with 0, 1 or multiple R₆.
 5. A compoundaccording to claim 2, wherein R₁ is chosen from alkyl and aryl, eachoptionally substituted with 0, 1 or multiple R₆, and R₂ is chosen fromhydrogen, alkyl, aryl, and acyl, each optionally substituted with 0, 1or multiple R₆.
 6. A compound according to claim 1, wherein X is C(O)R₃and Y is hydrogen.
 7. A compound according to claim 6, wherein R₁ ischosen from alkyl and aryl, each optionally substituted with 0, 1 ormultiple R₆.
 8. A compound according to claim 6, wherein R₂ is chosenfrom hydrogen, alkyl, aryl, and acyl, each optionally substituted with0, 1 or multiple R₆.
 9. A compound according to claim 6, wherein R₁ ischosen from alkyl and aryl, each optionally substituted with 0, 1 ormultiple R₆, and R₂ is chosen from hydrogen, alkyl, aryl, and acyl, eachoptionally substituted with 0, 1 or multiple R₆.
 10. A compoundaccording to claim 1, wherein X is hydrogen and Y is Q.
 11. A compoundaccording to claim 10, wherein R₄ is hydrogen.
 12. A compound accordingto claim 11, wherein R₁ is chosen from alkyl and aryl, each optionallysubstituted with 0, 1 or multiple R₆.
 13. A compound according to claim11, wherein R₂ is chosen from hydrogen, alkyl, aryl, and acyl, eachoptionally substituted with 0, 1 or multiple R₆.
 14. A compoundaccording to claim 11, wherein R₁ is chosen from and aryl, eachoptionally substituted with 0, 1 or multiple R₆, and R₂ is chosen fromhydrogen, alkyl, aryl, and acyl, each optionally substituted with 0, 1or multiple R₆.
 15. A compound according to claim 10, wherein R₄ is—C(O)R₅ or —CH₂OC(O)R₅.
 16. A compound according to claim 15, wherein R₅is chosen from alkyl and alkoxy, each optionally substituted with 0, 1,or multiple R₆.
 17. A compound according to claim 16, wherein R₁ ischosen from alkyl and aryl, each optionally substituted with 0, 1 ormultiple R₆.
 18. A compound according to claim 16, wherein R₂ is chosenfrom hydrogen, alkyl, aryl, and acyl, each optionally substituted with0, 1 or multiple R₆.
 19. A compound according to claim 16, wherein R₁ ischosen from alkyl and aryl, each optionally substituted with 0, 1 ormultiple R₆, and R₂ is chosen from hydrogen, alkyl, aryl, and acyl, eachoptionally substituted with 0, 1 or multiple R₆.
 20. A compoundaccording to claim 19, wherein R₅ is chosen from —CH₃, —CH₂OCH₂CH₃, and—CH₂CH₂OCH₃.
 21. A compound according to claim 1, wherein acyl refers to—C(═O)—CH(CH₃)₂.